2007 Basic and Clinical Awards
2007 Pilot Grants
2007 Basic and Clinical Awards
2007 Treatment Grants
Lorraine Bahrick, Ph.D.
Florida International University
$448, 972 for 3 years
Attention to Social and Nonsocial Events in Children with Autism
This research project will use the Behavioral Attention Assessment Protocol in children with autism to characterize early core attention deficits, and evaluate the ability of this measure to predict the nature and severity of later developing behaviors. Early attention will be assessed using sensory processing, disengagement, orienting, and maintenance of attention. Early preliminary data collected by Dr. Bahrick and her research group
suggest that children with autism show overall impairments in sensory processing as well as attention disengagement deficits specific to social events, particularly affectively neutral audiovisual speech. In addition to their measures of early attention, standard diagnostic measures of autism will be implemented to correlate early attentional deficits with symptom severity. This study will allow them to further extend their study and evaluate their assessment protocol for reliability and validity, allowing other clinicians to use it to assess early attentional deficits along with other measures to improve early diagnosis and prediction of behavioral development.
What this means for people with autism: Understanding core attention deficits in autism, their origins in infancy, and how they are related to social impairments seen in children with autism is critical to developing earlier and more effective interventions for social and communicative functioning.
Eric Courchesne, Ph.D.
University of California San Diego
$448,523 for 3 years
Stereological Analyses of Neuron Numbers in Frontal Cortex from Age 3 Years to Adulthood in Autism
Recent MRI studies suggest that the brain of a toddler with autism grows at an excessive rate, leaving the child with an enlarged brain volume relative to typically-developing toddlers. The frontal and temporal lobes are sites of maximal brain enlargement. The frontal lobe plays vital roles in higher-order cognitive, language, social, and emotional functions, each of which is seriously deficient in autistic subjects. One hypothesis to account for the enlargement is that the autistic brain has an excessive number of neurons. However, following the overgrowth phase, there is also evidence of a premature growth arrest in frontal lobes. Thus, there is the intriguing possibility that while there are an excessive number of neurons in autism during early childhood in frontal cortex, this phase is followed by a decline in numbers beginning by preadolescence.
The proposed study will test this hypothesis by carrying out a systematic stereological examination of the number of neurons in the entire frontal cortex as well as five well-defined frontal regions in 16 autistic and 16 control cases ages 2 years to 45 years, examining both group differences and age related changes in neuron number. In addition, since autism cases included in the study will have met ADI-R criteria, the investigators will carry out biostatistical analyses of the relationship between neuron numbers, clinical phenotypic information (from the ADI-R), and postmortem variables of interest (e.g., cause of death, post-mortem interval).
What this means for people with autism: The neural defects driving early brain overgrowth may underlie the behavioral and clinical emergence of autism. This study will begin to reveal the underlying developmental cellular and molecular defects that can contribute to the development of autistic behavior.
Mirella Dapretto, Ph.D.
University of California, Los Angeles
$300,000 for 2 years
A Combined fMRI-TMS Study on the Role of the Mirror Neuron System in Social Cognition: Moving Beyond Correlational Evidence
The mirror neuron system (MNS) is one of the neural systems in the brain involved in processing information that allows us to readily understand others' actions, intentions, and emotions. Recent studies have suggested dysfunction in the MNS may underlie the social impairments observed in autism spectrum disorders (ASD). However, the role of the MNS in social cognition is not yet conclusive. The aim of the proposed research is to address this fundamental issue by testing the relationship between brain activity and behavior using a combination of functional brain imaging (fMRI) and Transcranial Magnetic Stimulation (rTMS). rTMS delivers a non-harmful magnetic pulse that causes a transient (reversible) artificial disruption of normal brain activity and can target specific brain systems. In this study rTMS will be used to disrupt the function of selected parts of the MNS so as to provide information on whether activity in the MNS is necessary for successful emotion recognition in high-functioning individuals with ASD in comparison with neurotypical individuals.
What this means for people with autism: The study will provide insight into the biological mechanisms and brain systems that underlie autism spectrum disorders. It will address the important issue whether the functioning of the NMS system underlies the ability to automatically ‘read' others' minds and emotional recognition. This rigorous evaluation of the neural mechanisms associated with emotion understanding in the normal and autistic brain is a critical first step toward the design and implementation of interventions aimed at mitigating the significant impairments observed in autism in the social domain.
Gregory Essik, Ph.D.
University Of North Carolina
$434,622 for 3 years
Multisensory Processing in Autism
Autobiographical accounts of autism often emphasize difficulties with sensory input from the environment. Some reports also indicate a reduced ability to coherently merge sensory signals from two or more senses, resulting in a confusing, fragmented perceptual world and the impetus for social withdrawal. These studies importantly assess sensory functioning within the natural environment, but are limited by their subjective nature, which makes the findings difficult to link to underlying brain mechanisms. A natural complement to previous approaches is psychophysics, that is, the objective quantitative measurement of sensation and perception that can be linked to brain mechanisms.
In this study, Dr. Essik will use psychophysical techniques to study sensory processing both within a sensory system (the system for touch) and between the touch and visual systems. He will assess sensory sensitivity in groups of adults with and without autism for several types of stimuli. To understand the neural bases of these findings, the brain's responses to these stimuli will be studied using functional magnetic resonance imaging (fMRI). Stimuli will be presented either alone or simultaneously in order to detect their interactions. Based on pilot work, the researchers predict that sensitivity to the diverse forms of stimuli and their brain responses will be altered in autism.
What this means for people with autism: Characterization of altered sensory perception and sensory interactions is key to understanding the difficulties autistic individuals experience. It is also the first step toward the identification of novel therapeutic approaches from a sensory perspective.
Paul Gabbott, Ph.D.
Payam Rezaie, Ph.D.
Biological Sciences Department, The Open University
$424,528 for 3 years
Dendritic organization within the cerebral cortex in autism
Brain imaging studies in patients with ASD indicate that deficits in social cognition, language, communication and stereotypical behaviors may be related to functional alterations in specific brain regions, particularly the frontal and temporal cortical areas. Neuroanatomical and neuropathological investigations also point to early developmental abnormalities which affect cortical neuronal cytoarchitecture. Within the cerebral cortex, the cell bodies of neurons are organized radially into discrete cytoarchitectural units called ‘minicolumns'. Recent studies have revealed that minicolumns, and the neuronal cell bodies that make them up, are reorganized within the prefrontal, cingulate and inferior temporal cortices in autism. However, it is not known whether such structural reorganization also affects the distribution of dendrites (cellular processes) that originate from neurons in minicolumns, thereby critically altering the processing of neural information within these cortical areas.
This project will address the fundamental question of whether dendritic architecture is altered within regions of the cerebral cortex known to be affected in autism. Sophisticated image analysis will be carried out on defined cortical areas in post-mortem materials obtained from ASD and matched control cases (supplied by Autism Speaks' Autism Tissue Program). Using a coordinated and systematic approach, this project will obtain detailed insight into the extent to which information processing, at the level of select dendritic networks, is altered within functionally-defined areas of the cortex in ASD.
What this means for people with autism: These findings will determine whether the neurobiological basis for the core behavioral changes observed in ASD can be related to dendritic reorganization within the cerebral cortex. This helps guide future design of targeted biological treatments.
Daniel Glaze, M.D.
Baylor College Of Medicine
$450,000 for 3 years
Treatment of Sleep Problems in Children with Autism Spectrum Disorder with Melatonin: A Double-blind, placebo-controlled study
Children with ASD experience high rates of sleep disturbances that potentially contribute to problems with thinking and behavior. It is unclear whether changes in melatonin (MT) production cause sleep problems in children with ASD. MT is frequently used to treat these sleep problems; however, it has not been well established whether MT is an effective treatment. This study will examine whether sleep problems in children with autism spectrum disorder (ASD) are related to alterations in the production of melatonin, a hormone that plays an important role in regulating sleep-wake cycle. This study will also examine whether MT is effective in improving sleep in children with ASD. The two hypotheses that will be tested are: 1) Children with ASD and sleep problems will have a delayed sleep-wake cycle and/or decreased MT production compared with those without sleep problems; and 2) Treatment with MT will be associated with improved sleep and behavior. Sleep disturbance will be measured using a standardized questionnaire. The MT levels will be measured in saliva in two groups of children with ASD both with and without sleep problems. Total 24-hour MT production will be determined from urine samples in these same two groups. Eligible participants will then be enrolled in a trial of three oral doses of MT (3, 6, 9 mg) and a placebo. Neither children nor investigators will know which doses are being given to which participants. This study will also determine whether treatment with MT helps children fall asleep faster and whether their behavior improves.
What this means for people with autism: Results from this study will inform the development of future trials of sleep-wake interventions and clinical guidelines for the use of MT to manage sleep problems in ASD.
Michael Greenberg, Ph.D.
Children's Hospital Boston
$450,000 for 3 years
The Effects of Npas4 and Sema4D on Inhibitory Synapse Formation
During development, hundreds of proteins direct the formation and maintenance of synapses (connections between brain cells) that shape the proper circuitry of the brain. As synapses form, eliminate, and re-form, a precise balance between the inhibitory and excitatory synaptic inputs must be attained for accurate brain function. Mutations in the proteins that regulate synapse development give rise to defects in these processes and have been suggested to be responsible for disorders of human cognitive function such as Autism Spectrum Disorders (ASD).
Dr. Greenberg and colleagues have identified an activity-regulated gene Npas4 that encodes a protein required specifically for the formation of inhibitory synapses. However, the molecular mechanism by which Npas4 selectively controls the formation of inhibitory synapses remains unknown. This project will use mice deficient in Npas4 to gain insight into this process. Genome-wide screens will also be carried out to identify the genetic program that Npas4 regulates to promote inhibitory synapse formation. Special attention will be given to those genes that map to regions implicated in ASD by human linkage and association studies as they will be considered ASD candidate genes. The researchers hope to gain insights into the experience-dependent molecular processes responsible for ASD, and ultimately uncover therapies and cures for this devastating disease.
What this means to people with autism: To understand the causes of ASD and ultimately identify treatments and cures, it is important to understand the genetic and environmental cues that govern synapse development and create the proper balance between inhibition and excitation in the brain.
James Gusella, Ph.D.
Massachusetts General Hospital/ Harvard Medical School
$450,000 for 3 years
The Role of Neurexin 1 Gene in Susceptibility to Autism
Neurexin 1 (NRXN1) was recently implicated as an autism susceptibility gene. The association is intriguing because it interacts with neuroligin-3 and SHANK3, two other genes previously found to generate risk for autism and mental retardation, at synaptic junctions to help regulate synapse formation. Dr. Gusella and his colleagues plan to examine NRXN1 in samples from AGRE and samples collected by collaborators for mutations or variations that could disrupt its function and determine if it plays a role in a larger proportion of autism cases. In addition, since the samples will be clinically well characterized, there is also an opportunity to establish a more robust correlation between genetic variation and clinical presentation.
What this means for people with autism: This study could determine the impact of NRXN1 variation on autism risk and a better sense of its frequency in the autism community. Understanding how these variants affect protein function and synaptogenesis could shed light on the underlying disease mechanism.
Heather Cody Hazlett, Ph.D.
University of North Carolina
$449,226 for 3 years
MRI study of brain development in school age children with autism
Multiple lines of evidence indicate that brain enlargement in autism is a real phenomenon. However, the time course and pattern of this enlargement, and the relationship to clinical features, is not yet clear. It will be critically important to examine subjects over time (a longitudinal design) in order to characterize the trajectory of MRI brain development in conditions such as autism. Dr. Hazlett's research team at UNC has developed image processing tools specifically designed for highly-efficient, reliable and valid processing of pediatric MRI data. Their early results from a longitudinal MRI study of brain development demonstrate generalized enlargement of white and gray matter volume in cerebral cortex in autistic individuals at age 2 yrs.
This study will track brain development using MRI/DTI scans in 6-10 year olds with autism and controls who have already participated in the longitudinal MRI study of brain development. Forty-two children with autism who have been scanned at ages 2 and 4 will be rescanned at age 6-10. Controls will include typically developing children and a small subset of children with developmental delay. This study will provide more definitive information about the trajectory of brain growth (regions, tissues, structures and fiber tracts) as measured on MRI and DTI. Additionally, Dr. Hazlett will be able to explore behavioral features associated with social cognition and ritualistic repetitive behaviors in an in-depth manner now that the children are older (6-10 years old), which may provide important insights into the development of neurobiological mechanisms and behavioral phenotypes in autism.
What this means for people with autism: This study presents a unique opportunity to characterize brain growth from toddlerhood to school-age in individuals with autism. This will reveal the individual trajectory of brain development in autism and allow it to be linked to specific behavioral outcomes.
Kimberly Huber, Ph.D.
University of Texas Southwestern Medical Center
$450,000 for 3 years
Developmental versus Acute Mechanisms Mediating Altered Excitatory Synaptic Function in the Fragile X Syndrome Mouse Model
Fragile X Syndrome (FXS) is the most common inherited form of mental retardation and is caused by loss of function mutations in the Fmr1 gene. Approximately 30% of FXS patients are diagnosed with autism, and 2-5% of all autistic children have FXS. As result, Fmr1 is currently one of 3 most strongly linked genes to autism. Therefore, the mouse model of FXS may be useful in determining what causes or facilitates autism in humans. Virtually nothing is known about how the protein product of Fmr1, FMRP, or its loss, affects the development and function of brain circuitry.
Dr. Huber's lab utilizes electrophysiological methods that directly measure the electrical-chemical nature of neuronal communication in brain circuitry. The primary means of communication in brain circuits is the excitatory synapse. It is well established that synapses are plastic, in that they can alter their size, strength and number in both developing and adult brains. Dr. Huber's preliminary experiments provide evidence that excitatory synaptic communication is dramatically decreased in the Fmr1 mutant mouse brain during development. In this project the researchers will further characterize this phenomenon, identify the specific components of the excitatory synapse that are responsible for the decrease in synaptic communication, and test whether intervening with the molecular pathways will reduce the synaptic deficits found in the FXS mouse model.
What does this mean for people with autism: Further understanding of the synaptic impairments is critical for designing treatments and cures for FXS and perhaps autism. Identification of the molecular mechanisms that affect brain circuitry in a model of autism will directly lead to identification of therapeutic targets.
Harley Kornblum, M.D., Ph.D.
UCLA School of Medicine
$450,000 for 3 years
Molecular and Environmental Influences on Autism Pathophysiology
Multiple studies have reported abnormal brain growth in people with autism, reflected by a larger head size early in development. This feature, called “macrocephaly” is determined in part by the number of times a cell divides as the brain matures. Using a cell culture technique, this study will examine genetic mutations of two genes associated with autism, PTEN and TSC on cell size and number. In addition to genetic influences, environmental factors could influence head size and cell division in the developing brain through production of reactive oxygen species (ROS). At low doses that are not toxic to neurons, these molecules have been known to produce changes in cell number. The current study will examine if ROS stimulates cell division through a similar pathway as PTEN and TSC mutations. The effects of prenatal exposure to low levels of ROS on cells with and without mutations of the PTEN gene will be assessed in parallel models to determine the interaction of the two on both brain size and cell number.
What this means for people with autism: Both genetic susceptibility and environmental factors have been linked to the cause of autism. This research will help scientists understand the basic neurobiology behind enlarged head size in people with autism, as well as isolate a specific molecular mechanism where environmental influences can interact with genetic factors to produce macrocephaly.
Karen Kuhlthau, Ph.D.
Massachusetts General Hospital
$450,000 for 3 years
Quality of Life for Children with Autism Spectrum Disorders and their Parents
Health-realted quality of life (HRQoL) is a multidimensional measure of the effects of ilness on a patient, as perceived by the individual or proxy-reporter. This study will assess the HRQoL of children with ASD and that of their parents. Specifically, this study will assess the relationship of child HRQoL with measures of clinical severity, sleep disorders, behavior, and executive functioning. This study will also examine the relationship between parental quality of life scores with the child's HRQol and the child's clinical characteristics. A final goal will be to develop an autism-specific HRQoL measure for children.
This study will maximize the utility of the Autism Treatment Network (ATN), a multi-site collaborative program focused on establishing standards of medical care for ASD children. The ATN enrolls large numbers of children nationwide and provides a data registry comprised of standardized measures.
What this means for people with autism: A better understanding of the factors that predict an improved HRQoL for children with ASD could help clinicians better target treatment efforts. This, in turn, will impact the family and may lead to an improved quality of life across the family unit. Having an HRQoL tool that specifically addresses ASD children will provide a critical measure of outcome for use in future clinical and research trials.
Louis Kunkel, Ph.D.
Children's Hospital Boston
$450,000 for 3 years
Uncovering Genetic Mechanisms of ASD
Gene expression, or mRNA profiling, has been used successfully in cancer research to help characterize and categorize different types of neoplasia and predict such behaviors as responsiveness to treatment and likelihood of metastasis. Dr. Kunkel and colleagues plan to use expression profiling to explore the possibility of establishing “signatures” of gene expression that could distinguish individuals with autism from controls. In addition, he intends to examine splicing patterns of neuronal mRNA that could lead to pathogenesis to explore a possible mechanistic link with observed copy number variants (CNV).
What this means for people with autism: The identification of gene expression “signatures” for autism could inform the development of diagnostics like it has in cancer and opens the possibility of stratifying the population for targeted intervention.
Li-Ching Lee, Ph.D., Sc.M.
Johns Hopkins Bloomberg School of Public Health
$450,000 over three years
The Development of Chinese Versions of the ADOS and ADI-R
Of the available standardized diagnostic instruments for autism spectrum disorders, the Autism Diagnostic Observational Schedule (ADOS) and the Autism Diagnostic Interview- Revised (ADI-R) are the most commonly used. Currently, both the ADOS and ADI-R are available in twelve languages, and although Chinese mandarin is the primary language for 1.2 billion people worldwide, it is not available in this language. A previous project completed by a team of experts assembled by Dr. Lee has collected preliminary data from translated screening instruments such as the SCQ had identified cultural factors which should be modified to make the testing instrument valid. The unavailability of proper diagnostic tools in Chinese has been one of the major barriers for autism researchers who conduct research in Chinese speaking populations. To fill the gap and facilitate future autism research in Chinese speaking populations, this application will both translate and adapt the ADOS and ADI-R into Chinese mandarin and train Chinese-speaking clinicians to become research reliable on these diagnostic instruments so a later prevalence study can be conducted in this country.
What this means for people with autism: Data collected using the Chinese versions of the ADOS and ADI-R will allow multi-national and multi-racial/ethnic comparisons in variations and similarities of ASDs using the same diagnostic criteria and case definitions. This will allow researchers to examine the prevalence and incidence of autism in a country with different genetic and environmental factors to better understand the causes of autism.
Patricia Maness, Ph.D.
Biochemistry & Biophysics, School Of Medicine, UNC At Chapel Hill
$450,000 for 3 years
NrCAM, a Candidate Susceptibility Gene for Visual Processing Deficits in Autism
NrCAM, an axon guidance molecule (human chromosome 7q31.1 – 31.2), has been recently identified in genetic association studies as a candidate susceptibility gene for autism spectrum disorders (ASD). Abnormal visual processing may be causally related to ASD deficits of eye gaze and interpretation of facial expression, which contribute to impaired social interaction, and deficits in motion perception and movement toward visual stimuli. This project will provide insight into visual system development and its pathology associated with autism that may arise from mutations in the NrCAM gene.
Dr. Maness will study mutant mice lacking NrCAM to investigate the hypothesis that NrCAM mediates formation of the precise connections between the axons from the retina and their targets in the brain. This will serve as a potentially new model for visual processing deficits in ASD. This project will use a variety of molecular techniques to characterize in detail what happens to connections from the eye to the brain when NrCAM function is disrupted. Abnormalities in visual processing may also impair social communication and motor responses, thus NrCAM mutant mice and controls will be analyzed for behaviors relevant to ASD, including impaired sociability, sensorimotor gating, and learning.
What this means for people with autism: Knowledge gained from this research could contribute to the diagnosis and molecular understanding of autism, and will encourage genetic studies of NrCAM polymorphisms associated with autistic patient populations.
A. Kimberley McAllister, Ph.D.
University of California, Davis
$450,000 for 3 years
Immune molecules and cortical synaptogenesis: possible implications for the pathogenesis of autism
Proper formation of connections in the brain during childhood provides the substrate for adult perception, learning, memory, and cognition. Tragically, improper formation or function of these connections may lead to many neurodevelopmental disorders, including autism. Although there is clearly a strong genetic component to autism, its incidence also appears to be influenced by a wide range of environmental factors. Many of these factors have in common the ability to alter immune function. Since MHCI molecules are proteins that mediate the immune response and that are also present on neurons, it is possible that changes in expression of MHCI in the developing brain lead to the cellular changes that contribute to autism.
Recently, Dr. McAllister's lab has discovered that MHCI molecules negatively regulate the initial formation of connections in the developing brain. This result is particularly exciting because it implies that environmental factors that initiate an immune response could dramatically affect connectivity in the developing brain and thereby alter cognition. Since cytokines potently regulate MHCI expression in the immune system and several cytokines have been found to be upregulated in the brains of autistic children, it is possible that these cytokines alter synaptic connectivity in the developing brain by altering MHCI levels. This project will test this hypothesis.
What this means for people with autism: Results from these experiments will identify whether alterations in MHCI levels could be involved in the pathogenesis of autism. Elucidating the mechanisms by which MHCI molecules act could reveal possible therapeutic targets for preventing and/or treating autism. (Co-sponsor: The Higgins Family Charitable Foundation)
Thomas McDonald, M.D.
Albert Einstein College of Medicine of Yeshiva University
$450,000 for 3 years
Modeling and Pharmacologic Treatment of Autism Spectrum Disorders in Drosophila
It is important to develop laboratory based models of autism, since such models can be readily used to generate and test hypotheses, investigate, characterize and manipulate biological mechanisms in much more detail that would be possible using human subjects. Drosophila, the fruit fly, is such an advantageous experimental model and a high throughput system. The present study plans to create the Drosophila equivalent of the genetic abnormalities that underlie syndromes such as genes Rubinstein-Taybi syndrome, neurofibromatosis type 1, tuberous sclerosis complex type 1, tuberous sclerosis complex type 2 and Rett's syndrome – all of which are associated with autism spectrum disorders. The study will also examine any additional impact of a combination of one of these genes plus the fmr1 (Fragile X) gene. The study will examine what effects such genetic manipulations have on biochemical pathways in the brain, and how this relates to behaviors. The social and memory aspects of Drosophila courtship will be used as surrogate markers for impairments in social interactions and cognitive ability in autism. Alterations in the architecture of the brain areas that control these Drosophila behaviours will also be examined. Furthermore, the research seeks to identify pharmacological agents that can rescue the phenotype.
What this means for people with autism: The exploitation of the Drosophila equivalents to some of the genes and behaviors found in man represents a convenient high throughput model system that can be used to economically and rapidly manipulate genes, examine neurobiology and behaviors, and test pharmacological agents. Drosophila research can inform other animal studies and indeed human research.
Daniel Messinger, Ph.D.
University of Miami
$450,000 for 3 years
Automated Measurement of Facial Expression in Autism: Deficits in Facial Nerve Function?
Autism is a developmental disorder involving qualitative impairments in social interaction. One source of those impairments are difficulties creating facial expressions of emotion. Difficulties with facial expressions may arise from deficits in a motivation to express positive emotions with others. The difficulties may also stem from physiological problems in physically creating expressions that are due to damage to areas of the brain that control the facial nerve (which produces those expressions).
This project will utilize automated facial analysis software to compare how, when, and to what extent 20 four- to six year-old children with autistic disorder, 20 children with developmental disabilities, and 20 typically developing children produce facial expressions. Children will be observed playing social games with a tester and in a non-interactive context watching video clips and playing simple video games. These methods will provide insight in to the nature and possible source of the facial expressivity deficits expected in children with autism. If deficits are evident in an interaction setting but not when playing with video games, this would suggest deficits are related to an emotional motivation to engage. If deficits are apparent in both settings or are evenly distributed between positive, negative, and neutral expressive periods, this would suggest deficits are due to a physiological deficit.
What this means for people with autism: Discerning the probable source of difficulties in facial expressivity will provide a more complete understanding of social deficits in autism and suggest therapeutic approaches that are most appropriate for children with autism.
Cynthia Molloy, M.D.
Cincinnati Children's Hospital Medical Center
$449,742 for 3 years
Genome-wide Association Study of Autism Characterized by Developmental Regression
By some estimates, up to 30% of children with autism experienced developmental regression characterized by the acquisition and subsequent loss of social and communication skills. Dr. Molloy plans to explore the genetic component of this devastating phenomenon by analyzing and comparing the genetic “profile” of children with autism affected by regression with normally developing counterparts. By focusing on a more homogenous subset of the population, she and her colleagues hope to identify autism susceptibility genes, especially those that might be related to regression.
What this means for people with autism: If the subset of children who are likely to experience regression can be identified genetically, it could provide biomarkers for earlier diagnosis and aid in the development of intervention strategy related to those gene changes.
P. Read Montague, Ph.D.
Baylor College of Medicine
$450,000 for 3 years
Neural Correlates of Social Exchange and Valuation in Autism
Recent advances in brain imaging techniques mean that it is now possible to examine how the brain is functioning when an individual carries out a social ‘task' or exchange. Hyperscan functional magnetic resonance imaging (h-fMRI) i.e. the simultaneous measurement of brain activity in two socially interacting people, is an important development for autism research. The present study aims to combine computational approaches with functional brain imaging to examine how the neural systems involved in social interactions go awry to yield the social deficits seen in autism spectrum disorders.
Specifically, a social exchange task called an iterated Trust game and h-fMRI will be used to characterize neural and behavioral responses to social signals in individuals with autism as they participate in dynamic social exchanges with a human partner. The study will also use a ‘computer partner' to examine differences in the sensitivity of individuals with autism spectrum disorder to signals of social reciprocity - the computer partner will be made to vary its responses from ‘human-like and socially responsive' to ‘random and not socially-responsive'.
What this means to people with autism: The proposed work promises not only to contribute to the current understanding of the neural substrates of autism and its social sequelae but to provide a technological way to define new phenotypes and ultimately identify specific subtypes of autism spectrum disorders. This could inform the design, target, and implementation of new diagnostic and intervention protocols.
Glenn Rall, Ph.D.
The Fox Chase Cancer Center
$273,782 for 2 years
Consequences of Maternal Antigen Exposure on Offspring Immunity: An Animal Model of Vertical Tolerance
How pathogens and/or altered immune responses to pathogens or vaccines are related to the etiology of childhood autism remains unresolved. Recently, a chronic neuroinflammatory response was reported in some children with autism. In separate mouse studies, it was shown that maternal exposure to viral pathogens during pregnancy could adversely influence neurodevelopment in her offspring. Whether these findings are linked, and how they relate to the onset of autism, remain unresolved.
The goal of this pilot project is to perform basic science experiments in a mouse model of central nervous system infection with measles virus (MV) to explore the potential link between maternal immune history and neuroinflammation. In preliminary experiments, Dr. Rall has shown that neonatal mice born of mothers that were previously infected with MV had increased expression of pro-inflammatory molecules, including those observed in autistic children. Moreover, the neonates appeared to be immunological tolerant to further infection by MV. This project will further characterize these findings in greater detail to gain insight into the impact of human maternal immunity on the developing immune system of her progeny.
What this means for people with autism: This project will help define the role that altered immunity and chronic neuroinflammation play in the etiology of autism spectrum disorders.
Vijaya Ramesh, Ph.D.
Massachusetts General Hospital
$449,988 for 3 years
Role of Pam in Synaptic Morphology and Function
The co-occurrence of Autism Spectrum Disorders (ASD) and Tuberous Sclerosis Complex (TSC) has been recognized for many years. Features of ASD are present in 25-50% of individuals with TSC, a neurodevelopmental disorder caused by mutations in tumor suppressor genes TSC1 and TSC2, encoding hamartin and tuberin respectively. Tuberin and hamartin function together to inhibit mTOR signaling, which regulates protein synthesis and cell growth. In addition to being a critical regulator of cell growth, mTOR signaling plays an essential role in neural plasticity and synapse function by modulating local protein synthesis in neurons. Dr. Ramesh has identified another protein, Pam (Protein Associated with Myc), that interacts with the TSC2 protein tuberin and modulates mTOR as well.
The central hypothesis of this proposal is that Pam functions as an E3 ubiquitin ligase and controls the balance of synaptic proteins. The synapse, a basic unit of function in the nervous system is the primary site of communication between neurons. Aberrant expression of Pam could perturb this balance resulting in excess or reduced neuronal connectivity. Mutations in another E3 ligase have been reported in autism associated with Angelman's syndrome. These observations, as well as the link between TSC and autism, strongly support the hypothesis that Pam could be a potential player in ASD.
What this means to people with autism: This project is devoted to understanding the role of Pam in mammalian synapses as well as generating an animal model to serve as a valuable model for understanding how synaptic activity may be regulated in ASD.
James Rand, Ph.D.
Oklahoma Medical Research Foundation
$450,000 for 3 years
Role of Neuroligin in Synapse Stability
One of the most important results emerging from the intensive international effort to identify "autism-related" genes has been the demonstration of an association with autism (in some families) of mutations in genes encoding a family of proteins called neuroligins. Neuroligins are synaptic proteins present on post-synaptic cell membranes, and they bind specifically to a set of presynaptic membrane proteins called neurexins. Studies have shown that the binding of neuroligin to neurexin can be sufficient to mediate the assembly of the presynaptic components of a synapse. Mutations disrupting the NLGN3 and NLGN4 genes seem to be associated with autism. The association of autism with a disruption in components involved in synapse structure provides a point of entry for investigating the altered development and "miswiring" of the brain in autistic individuals.
This proposal will analyze the molecular genetics and cell biology of neuroligin and its role in synapse maintenance in the nematode C. elegans. Using this simple model system, the researchers will be addressing basic issues about the function of neuroligin in the development of the nervous system. Specifically they will study how synapses are impacted by the absence of neuroligin, what other molecules function with neuroligin to regulate synapse stability, and whether adding back neuroligin to the adult organism can rescue the abnormal development which occurred in its absence.
What this means for people with autism: Understanding the function of neuroligin in better detail will reveal the molecular pathways that are disrupted in autism and provide the information needed to design strategies to remediate the biological underpinnings of autism.
Donald Rojas, Ph.D.
University Of Colorado Health Sciences Center
$184,089 for 3 years
Gamma band dysfunction as a local neuronal connectivity endophenotype in autism
It has been proposed that general abnormalities in structural and functional neuronal connectivity may underlie many of the triad of deficits observed in autism. For example, weak central coherence and abnormal temporal binding may be related to alterations in brain functional and/or structural connectivity. Gamma band oscillatory activity, as measured using EEG and magnetoencephalography (MEG), is thought to play an important role in binding and central coherence. Some experiments have demonstrated that gamma activity is abnormal in people with autism, possibly reflecting a cortical GABA dysfunction.
Using a whole-head MEG system, the investigators will study activity within the auditory cortex and estimate patterns of cortical synchronization and desynchronization with high precision in both time and frequency. In order to uncover new endophenotypes for autism and the broader spectrum, the researchers will also study parents of affected individuals. Parents of children with autism will be assessed using MEG measures of gamma-band activity in motor and auditory tasks. Their data will be compared to matched adults with no family history of autism spectrum disorders and to matched adults with autism. MEG measures of gamma power and phase-locking will be measured and associated with their structural underpinnings from magnetic resonance imaging (MRI) data.
What this means for people with autism: This project will search for broad patterns of abnormal brain activity in individuals with autism and their family members, which may lead to new ways of diagnosing the disorder.
Erik Ullian, Ph.D.
University of California, San Francisco
$449,344 for 3 years
Role of Micro-RNAs in ASD Affected Circuit Formation and Function
Fragile X syndrome is a common disorder with clear relevance to autism spectrum disorders (ASD). Recently, it was discovered that the protein underlying this syndrome, FMRP, plays important regulatory roles in neuronal translation of RNA into protein. This discovery has opened up tremendous opportunity to study related mechanisms that are likely to be associated with autism. One common, but poorly understood, mechanism of translational control involves endogenous small RNAs. Small RNAs, including microRNAs (miRNAs) are expressed during development and through adulthood and it is clear that they play important regulatory roles in neuronal function. The greatest variety of miRNAs are expressed in the nervous system, including the cortex and cerebellum, making it paramount to understand what role miRNAs play in normal neuronal function and disease.
To date only two miRNA has been investigated in hippocampal neurons in vitro and these miRNA were found to regulate process outgrowth and synapse formation. Importantly, computational analyses of likely targets of their action indicate that numerous signaling pathways impacting neuronal function are regulated by miRNAs. Because cortical pyramidal and cerebellar Purkinje neurons are consistently affected in ASD, this project will use the power of mouse genetics to initially remove all miRNAs from cortical circuits and cerebellar Purkinje neurons after they have developed and ask what role miRNAs play in neuron survival, synaptic connectivity, and function.
What this means for people with autism: This project investigates the potential involvement in autism of a newly discovered pathway that regulates brain function. By focusing on the molecular mechanisms of the disorder, targeted therapeutic strategies for intervention can be developed.
Flora Vaccarino, M.D.
Yale University
$446,744 for 3 years
Neurogenic Growth Factor in Autism
In addition to their prominent role in certain types of cancer, genes in the fibroblast growth factor (FGF) pathway have been shown in animal models to be important for brain development. Animals with mutations in FGF genes, for instance, exhibit anatomical characteristics reminiscent of those observed in autism. Dr. Vaccarino plans to interrogate these genes for variants associated with autism. Using samples she collected as well as those from AGRE, she also plans to correlate changes in these genes associated with autism with changes in brain size and structures.
What this means for people with autism: If FGF genes are confirmed as genetic risk factors, autism research could benefit greatly from a wealth of information already available from a well characterized disease-causing mechanism, which could speed the development of targeted therapeutics.
Fred Volkmar, M.D.
Yale Child Study Center
$450,000 for 3 years
A Randomized Controlled Trial of Two Treatments for Verbal Communication
This study will examine the relative effectiveness of two communication interventions on the production of speech in 40 preschool children with ASD (3 to 6 years) who are pre-linguistic i.e. produce fewer than 10 different words. The two experimental treatments will be added to whatever interventions the child is receiving the community. The primary aim is to assess the effectiveness of a direct speech-focused treatment versus a naturalistic approach on the production of speech and the adaptive use of verbal communication. The study will also determine the effect of a parent-delivered generalization program on the maintenance of gains of the interventions provided.
The two treatments that will be compared are a direct speech-focused treatment, the Rapid Motor Imitation Training, that reinforces motor imitation (and later targets verbal requests and labels) versus a naturalistic approach the Prelinguistic Milieu Teaching (PMT), which has been demonstrated to be effective in increasing communicative behavior in young children with various developmental disabilities. At the end of the treatment period, the children will be assessed by the number of spoken words and expressive communication level. Further, in an effort to match child traits to the most appropriate treatment approach, the data will be analyzed to determine which child characteristics prior to the intervention are associated with greater gains in either of the two treatments.
What this means for people with autism: This project aims to compare the effectiveness of two established behavioral treatments aimed at improving language and communication abilities in preverbal, preschool children with ASD. It will advance evidence-based practice in the early intervention arena. It will also supply useful information for predicting the best treatment method to use with children who have particular profiles of prelinguistic development, so as to provide the most effective match between child and intervention.
Harland Winter, M.D.
Harvard Medical School
$450,000 for 3 years
Identifying Gastrointestinal (GI) Conditions in Children with Autism Spectrum Disorders (ASD)
Gastrointestinal (GI) dysfunction is relatively prevalent in children with ASD, but is especially difficult to diagnose, not only because of the social and communication deficits which prevent effective reporting of symptoms, but also the difficulties clinicians face in correlating behavior with specific GI disorders. Current clinical practice guidelines include neither routine GI evaluation nor diagnostic criteria or protocols that consider the special gastrointestinal needs of this patient population.
Therefore, the first objective of the proposed study is to develop and validate effective and appropriate diagnostic screening methods to detect symptomatic GI dysfunction in children with ASD. The second objective of the proposed research is to determine whether gastrointestinal (GI) dysfunction contributes substantially to the expression of problem behaviors (PB) in children with ASD and to determine, if specific behaviors, including but not limited to PB, are increased in those children with gastrointestinal dysfunctions. The main hypothesis to be tested is that painful or discomfort-causing gastrointestinal (GI) dysfunction occurs frequently in children with ASD, and contributes to an elevated incidence or severity of PB in an identifiable subpopulation of these children.
What this means for people with autism: The results of the study will inform the medical community about the prevalence of GI symtpoms as they relate to autism and will provide evidence that will inform clinical practice guidelines for children with ASD, thereby improving quality of life for these young patients and their family members.
Anthony Zador, M.D., Ph.D.
Cold Spring Harbor Laboratory
$450,000 for 3 years
Analysis of Cortical Circuits Related to ASD Gene Candidates
Although autism is among the most heritable of the common neuropsychiatric disorders, it is increasingly clear that no single gene mutation is responsible for all or even most cases. A growing number of genes have been implicated in the etiology of autism, but the candidate genes form a very heterogeneous collection. What do these genes have in common? What is the “final common pathway” that leads to autism? We hypothesize that this heterogeneous collection of autism gene candidates leads to dysfunction at the level of neural circuitry that is more homogeneous and thus easier to understand.
This project aims to develop an efficient way of studying, in rodents, the deficits in neural circuitry resulting from the perturbation of autism candidate genes. The investigators will disrupt the function of candidate autism genes and use a combination of in vitro and in vivo technologies to probe for circuit level effects. They will use this strategy to test a leading hypothesis about the circuit dysfunction underlying autism, namely that autism results in a functional imbalance between excitatory and inhibitory synaptic activity. Rat auditory cortex will be used as a model system. Sensory abnormalities, particularly in the auditory domain, are one of the characteristic signs of autism. The initial focus will be on the neuroligins, a candidate gene family implicated in autism. In summary, this project proposes to develop a general and efficient strategy for relating genetic and physiological dysfunction in rodent models of autism.
What this means for people with autism: Although the causes of autism may be many, understanding the circuit effects of autism genes will lead to a better understanding of how treatments can be designed to target the common biological mechanisms underlying autism.
Florida International University
$448, 972 for 3 years
Attention to Social and Nonsocial Events in Children with Autism
This research project will use the Behavioral Attention Assessment Protocol in children with autism to characterize early core attention deficits, and evaluate the ability of this measure to predict the nature and severity of later developing behaviors. Early attention will be assessed using sensory processing, disengagement, orienting, and maintenance of attention. Early preliminary data collected by Dr. Bahrick and her research group
suggest that children with autism show overall impairments in sensory processing as well as attention disengagement deficits specific to social events, particularly affectively neutral audiovisual speech. In addition to their measures of early attention, standard diagnostic measures of autism will be implemented to correlate early attentional deficits with symptom severity. This study will allow them to further extend their study and evaluate their assessment protocol for reliability and validity, allowing other clinicians to use it to assess early attentional deficits along with other measures to improve early diagnosis and prediction of behavioral development.
What this means for people with autism: Understanding core attention deficits in autism, their origins in infancy, and how they are related to social impairments seen in children with autism is critical to developing earlier and more effective interventions for social and communicative functioning.
Eric Courchesne, Ph.D.
University of California San Diego
$448,523 for 3 years
Stereological Analyses of Neuron Numbers in Frontal Cortex from Age 3 Years to Adulthood in Autism
Recent MRI studies suggest that the brain of a toddler with autism grows at an excessive rate, leaving the child with an enlarged brain volume relative to typically-developing toddlers. The frontal and temporal lobes are sites of maximal brain enlargement. The frontal lobe plays vital roles in higher-order cognitive, language, social, and emotional functions, each of which is seriously deficient in autistic subjects. One hypothesis to account for the enlargement is that the autistic brain has an excessive number of neurons. However, following the overgrowth phase, there is also evidence of a premature growth arrest in frontal lobes. Thus, there is the intriguing possibility that while there are an excessive number of neurons in autism during early childhood in frontal cortex, this phase is followed by a decline in numbers beginning by preadolescence.
The proposed study will test this hypothesis by carrying out a systematic stereological examination of the number of neurons in the entire frontal cortex as well as five well-defined frontal regions in 16 autistic and 16 control cases ages 2 years to 45 years, examining both group differences and age related changes in neuron number. In addition, since autism cases included in the study will have met ADI-R criteria, the investigators will carry out biostatistical analyses of the relationship between neuron numbers, clinical phenotypic information (from the ADI-R), and postmortem variables of interest (e.g., cause of death, post-mortem interval).
What this means for people with autism: The neural defects driving early brain overgrowth may underlie the behavioral and clinical emergence of autism. This study will begin to reveal the underlying developmental cellular and molecular defects that can contribute to the development of autistic behavior.
Mirella Dapretto, Ph.D.
University of California, Los Angeles
$300,000 for 2 years
A Combined fMRI-TMS Study on the Role of the Mirror Neuron System in Social Cognition: Moving Beyond Correlational Evidence
The mirror neuron system (MNS) is one of the neural systems in the brain involved in processing information that allows us to readily understand others' actions, intentions, and emotions. Recent studies have suggested dysfunction in the MNS may underlie the social impairments observed in autism spectrum disorders (ASD). However, the role of the MNS in social cognition is not yet conclusive. The aim of the proposed research is to address this fundamental issue by testing the relationship between brain activity and behavior using a combination of functional brain imaging (fMRI) and Transcranial Magnetic Stimulation (rTMS). rTMS delivers a non-harmful magnetic pulse that causes a transient (reversible) artificial disruption of normal brain activity and can target specific brain systems. In this study rTMS will be used to disrupt the function of selected parts of the MNS so as to provide information on whether activity in the MNS is necessary for successful emotion recognition in high-functioning individuals with ASD in comparison with neurotypical individuals.
What this means for people with autism: The study will provide insight into the biological mechanisms and brain systems that underlie autism spectrum disorders. It will address the important issue whether the functioning of the NMS system underlies the ability to automatically ‘read' others' minds and emotional recognition. This rigorous evaluation of the neural mechanisms associated with emotion understanding in the normal and autistic brain is a critical first step toward the design and implementation of interventions aimed at mitigating the significant impairments observed in autism in the social domain.
Gregory Essik, Ph.D.
University Of North Carolina
$434,622 for 3 years
Multisensory Processing in Autism
Autobiographical accounts of autism often emphasize difficulties with sensory input from the environment. Some reports also indicate a reduced ability to coherently merge sensory signals from two or more senses, resulting in a confusing, fragmented perceptual world and the impetus for social withdrawal. These studies importantly assess sensory functioning within the natural environment, but are limited by their subjective nature, which makes the findings difficult to link to underlying brain mechanisms. A natural complement to previous approaches is psychophysics, that is, the objective quantitative measurement of sensation and perception that can be linked to brain mechanisms.
In this study, Dr. Essik will use psychophysical techniques to study sensory processing both within a sensory system (the system for touch) and between the touch and visual systems. He will assess sensory sensitivity in groups of adults with and without autism for several types of stimuli. To understand the neural bases of these findings, the brain's responses to these stimuli will be studied using functional magnetic resonance imaging (fMRI). Stimuli will be presented either alone or simultaneously in order to detect their interactions. Based on pilot work, the researchers predict that sensitivity to the diverse forms of stimuli and their brain responses will be altered in autism.
What this means for people with autism: Characterization of altered sensory perception and sensory interactions is key to understanding the difficulties autistic individuals experience. It is also the first step toward the identification of novel therapeutic approaches from a sensory perspective.
Paul Gabbott, Ph.D.
Payam Rezaie, Ph.D.
Biological Sciences Department, The Open University
$424,528 for 3 years
Dendritic organization within the cerebral cortex in autism
Brain imaging studies in patients with ASD indicate that deficits in social cognition, language, communication and stereotypical behaviors may be related to functional alterations in specific brain regions, particularly the frontal and temporal cortical areas. Neuroanatomical and neuropathological investigations also point to early developmental abnormalities which affect cortical neuronal cytoarchitecture. Within the cerebral cortex, the cell bodies of neurons are organized radially into discrete cytoarchitectural units called ‘minicolumns'. Recent studies have revealed that minicolumns, and the neuronal cell bodies that make them up, are reorganized within the prefrontal, cingulate and inferior temporal cortices in autism. However, it is not known whether such structural reorganization also affects the distribution of dendrites (cellular processes) that originate from neurons in minicolumns, thereby critically altering the processing of neural information within these cortical areas.
This project will address the fundamental question of whether dendritic architecture is altered within regions of the cerebral cortex known to be affected in autism. Sophisticated image analysis will be carried out on defined cortical areas in post-mortem materials obtained from ASD and matched control cases (supplied by Autism Speaks' Autism Tissue Program). Using a coordinated and systematic approach, this project will obtain detailed insight into the extent to which information processing, at the level of select dendritic networks, is altered within functionally-defined areas of the cortex in ASD.
What this means for people with autism: These findings will determine whether the neurobiological basis for the core behavioral changes observed in ASD can be related to dendritic reorganization within the cerebral cortex. This helps guide future design of targeted biological treatments.
Daniel Glaze, M.D.
Baylor College Of Medicine
$450,000 for 3 years
Treatment of Sleep Problems in Children with Autism Spectrum Disorder with Melatonin: A Double-blind, placebo-controlled study
Children with ASD experience high rates of sleep disturbances that potentially contribute to problems with thinking and behavior. It is unclear whether changes in melatonin (MT) production cause sleep problems in children with ASD. MT is frequently used to treat these sleep problems; however, it has not been well established whether MT is an effective treatment. This study will examine whether sleep problems in children with autism spectrum disorder (ASD) are related to alterations in the production of melatonin, a hormone that plays an important role in regulating sleep-wake cycle. This study will also examine whether MT is effective in improving sleep in children with ASD. The two hypotheses that will be tested are: 1) Children with ASD and sleep problems will have a delayed sleep-wake cycle and/or decreased MT production compared with those without sleep problems; and 2) Treatment with MT will be associated with improved sleep and behavior. Sleep disturbance will be measured using a standardized questionnaire. The MT levels will be measured in saliva in two groups of children with ASD both with and without sleep problems. Total 24-hour MT production will be determined from urine samples in these same two groups. Eligible participants will then be enrolled in a trial of three oral doses of MT (3, 6, 9 mg) and a placebo. Neither children nor investigators will know which doses are being given to which participants. This study will also determine whether treatment with MT helps children fall asleep faster and whether their behavior improves.
What this means for people with autism: Results from this study will inform the development of future trials of sleep-wake interventions and clinical guidelines for the use of MT to manage sleep problems in ASD.
Michael Greenberg, Ph.D.
Children's Hospital Boston
$450,000 for 3 years
The Effects of Npas4 and Sema4D on Inhibitory Synapse Formation
During development, hundreds of proteins direct the formation and maintenance of synapses (connections between brain cells) that shape the proper circuitry of the brain. As synapses form, eliminate, and re-form, a precise balance between the inhibitory and excitatory synaptic inputs must be attained for accurate brain function. Mutations in the proteins that regulate synapse development give rise to defects in these processes and have been suggested to be responsible for disorders of human cognitive function such as Autism Spectrum Disorders (ASD).
Dr. Greenberg and colleagues have identified an activity-regulated gene Npas4 that encodes a protein required specifically for the formation of inhibitory synapses. However, the molecular mechanism by which Npas4 selectively controls the formation of inhibitory synapses remains unknown. This project will use mice deficient in Npas4 to gain insight into this process. Genome-wide screens will also be carried out to identify the genetic program that Npas4 regulates to promote inhibitory synapse formation. Special attention will be given to those genes that map to regions implicated in ASD by human linkage and association studies as they will be considered ASD candidate genes. The researchers hope to gain insights into the experience-dependent molecular processes responsible for ASD, and ultimately uncover therapies and cures for this devastating disease.
What this means to people with autism: To understand the causes of ASD and ultimately identify treatments and cures, it is important to understand the genetic and environmental cues that govern synapse development and create the proper balance between inhibition and excitation in the brain.
James Gusella, Ph.D.
Massachusetts General Hospital/ Harvard Medical School
$450,000 for 3 years
The Role of Neurexin 1 Gene in Susceptibility to Autism
Neurexin 1 (NRXN1) was recently implicated as an autism susceptibility gene. The association is intriguing because it interacts with neuroligin-3 and SHANK3, two other genes previously found to generate risk for autism and mental retardation, at synaptic junctions to help regulate synapse formation. Dr. Gusella and his colleagues plan to examine NRXN1 in samples from AGRE and samples collected by collaborators for mutations or variations that could disrupt its function and determine if it plays a role in a larger proportion of autism cases. In addition, since the samples will be clinically well characterized, there is also an opportunity to establish a more robust correlation between genetic variation and clinical presentation.
What this means for people with autism: This study could determine the impact of NRXN1 variation on autism risk and a better sense of its frequency in the autism community. Understanding how these variants affect protein function and synaptogenesis could shed light on the underlying disease mechanism.
Heather Cody Hazlett, Ph.D.
University of North Carolina
$449,226 for 3 years
MRI study of brain development in school age children with autism
Multiple lines of evidence indicate that brain enlargement in autism is a real phenomenon. However, the time course and pattern of this enlargement, and the relationship to clinical features, is not yet clear. It will be critically important to examine subjects over time (a longitudinal design) in order to characterize the trajectory of MRI brain development in conditions such as autism. Dr. Hazlett's research team at UNC has developed image processing tools specifically designed for highly-efficient, reliable and valid processing of pediatric MRI data. Their early results from a longitudinal MRI study of brain development demonstrate generalized enlargement of white and gray matter volume in cerebral cortex in autistic individuals at age 2 yrs.
This study will track brain development using MRI/DTI scans in 6-10 year olds with autism and controls who have already participated in the longitudinal MRI study of brain development. Forty-two children with autism who have been scanned at ages 2 and 4 will be rescanned at age 6-10. Controls will include typically developing children and a small subset of children with developmental delay. This study will provide more definitive information about the trajectory of brain growth (regions, tissues, structures and fiber tracts) as measured on MRI and DTI. Additionally, Dr. Hazlett will be able to explore behavioral features associated with social cognition and ritualistic repetitive behaviors in an in-depth manner now that the children are older (6-10 years old), which may provide important insights into the development of neurobiological mechanisms and behavioral phenotypes in autism.
What this means for people with autism: This study presents a unique opportunity to characterize brain growth from toddlerhood to school-age in individuals with autism. This will reveal the individual trajectory of brain development in autism and allow it to be linked to specific behavioral outcomes.
Kimberly Huber, Ph.D.
University of Texas Southwestern Medical Center
$450,000 for 3 years
Developmental versus Acute Mechanisms Mediating Altered Excitatory Synaptic Function in the Fragile X Syndrome Mouse Model
Fragile X Syndrome (FXS) is the most common inherited form of mental retardation and is caused by loss of function mutations in the Fmr1 gene. Approximately 30% of FXS patients are diagnosed with autism, and 2-5% of all autistic children have FXS. As result, Fmr1 is currently one of 3 most strongly linked genes to autism. Therefore, the mouse model of FXS may be useful in determining what causes or facilitates autism in humans. Virtually nothing is known about how the protein product of Fmr1, FMRP, or its loss, affects the development and function of brain circuitry.
Dr. Huber's lab utilizes electrophysiological methods that directly measure the electrical-chemical nature of neuronal communication in brain circuitry. The primary means of communication in brain circuits is the excitatory synapse. It is well established that synapses are plastic, in that they can alter their size, strength and number in both developing and adult brains. Dr. Huber's preliminary experiments provide evidence that excitatory synaptic communication is dramatically decreased in the Fmr1 mutant mouse brain during development. In this project the researchers will further characterize this phenomenon, identify the specific components of the excitatory synapse that are responsible for the decrease in synaptic communication, and test whether intervening with the molecular pathways will reduce the synaptic deficits found in the FXS mouse model.
What does this mean for people with autism: Further understanding of the synaptic impairments is critical for designing treatments and cures for FXS and perhaps autism. Identification of the molecular mechanisms that affect brain circuitry in a model of autism will directly lead to identification of therapeutic targets.
Harley Kornblum, M.D., Ph.D.
UCLA School of Medicine
$450,000 for 3 years
Molecular and Environmental Influences on Autism Pathophysiology
Multiple studies have reported abnormal brain growth in people with autism, reflected by a larger head size early in development. This feature, called “macrocephaly” is determined in part by the number of times a cell divides as the brain matures. Using a cell culture technique, this study will examine genetic mutations of two genes associated with autism, PTEN and TSC on cell size and number. In addition to genetic influences, environmental factors could influence head size and cell division in the developing brain through production of reactive oxygen species (ROS). At low doses that are not toxic to neurons, these molecules have been known to produce changes in cell number. The current study will examine if ROS stimulates cell division through a similar pathway as PTEN and TSC mutations. The effects of prenatal exposure to low levels of ROS on cells with and without mutations of the PTEN gene will be assessed in parallel models to determine the interaction of the two on both brain size and cell number.
What this means for people with autism: Both genetic susceptibility and environmental factors have been linked to the cause of autism. This research will help scientists understand the basic neurobiology behind enlarged head size in people with autism, as well as isolate a specific molecular mechanism where environmental influences can interact with genetic factors to produce macrocephaly.
Karen Kuhlthau, Ph.D.
Massachusetts General Hospital
$450,000 for 3 years
Quality of Life for Children with Autism Spectrum Disorders and their Parents
Health-realted quality of life (HRQoL) is a multidimensional measure of the effects of ilness on a patient, as perceived by the individual or proxy-reporter. This study will assess the HRQoL of children with ASD and that of their parents. Specifically, this study will assess the relationship of child HRQoL with measures of clinical severity, sleep disorders, behavior, and executive functioning. This study will also examine the relationship between parental quality of life scores with the child's HRQol and the child's clinical characteristics. A final goal will be to develop an autism-specific HRQoL measure for children.
This study will maximize the utility of the Autism Treatment Network (ATN), a multi-site collaborative program focused on establishing standards of medical care for ASD children. The ATN enrolls large numbers of children nationwide and provides a data registry comprised of standardized measures.
What this means for people with autism: A better understanding of the factors that predict an improved HRQoL for children with ASD could help clinicians better target treatment efforts. This, in turn, will impact the family and may lead to an improved quality of life across the family unit. Having an HRQoL tool that specifically addresses ASD children will provide a critical measure of outcome for use in future clinical and research trials.
Louis Kunkel, Ph.D.
Children's Hospital Boston
$450,000 for 3 years
Uncovering Genetic Mechanisms of ASD
Gene expression, or mRNA profiling, has been used successfully in cancer research to help characterize and categorize different types of neoplasia and predict such behaviors as responsiveness to treatment and likelihood of metastasis. Dr. Kunkel and colleagues plan to use expression profiling to explore the possibility of establishing “signatures” of gene expression that could distinguish individuals with autism from controls. In addition, he intends to examine splicing patterns of neuronal mRNA that could lead to pathogenesis to explore a possible mechanistic link with observed copy number variants (CNV).
What this means for people with autism: The identification of gene expression “signatures” for autism could inform the development of diagnostics like it has in cancer and opens the possibility of stratifying the population for targeted intervention.
Li-Ching Lee, Ph.D., Sc.M.
Johns Hopkins Bloomberg School of Public Health
$450,000 over three years
The Development of Chinese Versions of the ADOS and ADI-R
Of the available standardized diagnostic instruments for autism spectrum disorders, the Autism Diagnostic Observational Schedule (ADOS) and the Autism Diagnostic Interview- Revised (ADI-R) are the most commonly used. Currently, both the ADOS and ADI-R are available in twelve languages, and although Chinese mandarin is the primary language for 1.2 billion people worldwide, it is not available in this language. A previous project completed by a team of experts assembled by Dr. Lee has collected preliminary data from translated screening instruments such as the SCQ had identified cultural factors which should be modified to make the testing instrument valid. The unavailability of proper diagnostic tools in Chinese has been one of the major barriers for autism researchers who conduct research in Chinese speaking populations. To fill the gap and facilitate future autism research in Chinese speaking populations, this application will both translate and adapt the ADOS and ADI-R into Chinese mandarin and train Chinese-speaking clinicians to become research reliable on these diagnostic instruments so a later prevalence study can be conducted in this country.
What this means for people with autism: Data collected using the Chinese versions of the ADOS and ADI-R will allow multi-national and multi-racial/ethnic comparisons in variations and similarities of ASDs using the same diagnostic criteria and case definitions. This will allow researchers to examine the prevalence and incidence of autism in a country with different genetic and environmental factors to better understand the causes of autism.
Patricia Maness, Ph.D.
Biochemistry & Biophysics, School Of Medicine, UNC At Chapel Hill
$450,000 for 3 years
NrCAM, a Candidate Susceptibility Gene for Visual Processing Deficits in Autism
NrCAM, an axon guidance molecule (human chromosome 7q31.1 – 31.2), has been recently identified in genetic association studies as a candidate susceptibility gene for autism spectrum disorders (ASD). Abnormal visual processing may be causally related to ASD deficits of eye gaze and interpretation of facial expression, which contribute to impaired social interaction, and deficits in motion perception and movement toward visual stimuli. This project will provide insight into visual system development and its pathology associated with autism that may arise from mutations in the NrCAM gene.
Dr. Maness will study mutant mice lacking NrCAM to investigate the hypothesis that NrCAM mediates formation of the precise connections between the axons from the retina and their targets in the brain. This will serve as a potentially new model for visual processing deficits in ASD. This project will use a variety of molecular techniques to characterize in detail what happens to connections from the eye to the brain when NrCAM function is disrupted. Abnormalities in visual processing may also impair social communication and motor responses, thus NrCAM mutant mice and controls will be analyzed for behaviors relevant to ASD, including impaired sociability, sensorimotor gating, and learning.
What this means for people with autism: Knowledge gained from this research could contribute to the diagnosis and molecular understanding of autism, and will encourage genetic studies of NrCAM polymorphisms associated with autistic patient populations.
A. Kimberley McAllister, Ph.D.
University of California, Davis
$450,000 for 3 years
Immune molecules and cortical synaptogenesis: possible implications for the pathogenesis of autism
Proper formation of connections in the brain during childhood provides the substrate for adult perception, learning, memory, and cognition. Tragically, improper formation or function of these connections may lead to many neurodevelopmental disorders, including autism. Although there is clearly a strong genetic component to autism, its incidence also appears to be influenced by a wide range of environmental factors. Many of these factors have in common the ability to alter immune function. Since MHCI molecules are proteins that mediate the immune response and that are also present on neurons, it is possible that changes in expression of MHCI in the developing brain lead to the cellular changes that contribute to autism.
Recently, Dr. McAllister's lab has discovered that MHCI molecules negatively regulate the initial formation of connections in the developing brain. This result is particularly exciting because it implies that environmental factors that initiate an immune response could dramatically affect connectivity in the developing brain and thereby alter cognition. Since cytokines potently regulate MHCI expression in the immune system and several cytokines have been found to be upregulated in the brains of autistic children, it is possible that these cytokines alter synaptic connectivity in the developing brain by altering MHCI levels. This project will test this hypothesis.
What this means for people with autism: Results from these experiments will identify whether alterations in MHCI levels could be involved in the pathogenesis of autism. Elucidating the mechanisms by which MHCI molecules act could reveal possible therapeutic targets for preventing and/or treating autism. (Co-sponsor: The Higgins Family Charitable Foundation)
Thomas McDonald, M.D.
Albert Einstein College of Medicine of Yeshiva University
$450,000 for 3 years
Modeling and Pharmacologic Treatment of Autism Spectrum Disorders in Drosophila
It is important to develop laboratory based models of autism, since such models can be readily used to generate and test hypotheses, investigate, characterize and manipulate biological mechanisms in much more detail that would be possible using human subjects. Drosophila, the fruit fly, is such an advantageous experimental model and a high throughput system. The present study plans to create the Drosophila equivalent of the genetic abnormalities that underlie syndromes such as genes Rubinstein-Taybi syndrome, neurofibromatosis type 1, tuberous sclerosis complex type 1, tuberous sclerosis complex type 2 and Rett's syndrome – all of which are associated with autism spectrum disorders. The study will also examine any additional impact of a combination of one of these genes plus the fmr1 (Fragile X) gene. The study will examine what effects such genetic manipulations have on biochemical pathways in the brain, and how this relates to behaviors. The social and memory aspects of Drosophila courtship will be used as surrogate markers for impairments in social interactions and cognitive ability in autism. Alterations in the architecture of the brain areas that control these Drosophila behaviours will also be examined. Furthermore, the research seeks to identify pharmacological agents that can rescue the phenotype.
What this means for people with autism: The exploitation of the Drosophila equivalents to some of the genes and behaviors found in man represents a convenient high throughput model system that can be used to economically and rapidly manipulate genes, examine neurobiology and behaviors, and test pharmacological agents. Drosophila research can inform other animal studies and indeed human research.
Daniel Messinger, Ph.D.
University of Miami
$450,000 for 3 years
Automated Measurement of Facial Expression in Autism: Deficits in Facial Nerve Function?
Autism is a developmental disorder involving qualitative impairments in social interaction. One source of those impairments are difficulties creating facial expressions of emotion. Difficulties with facial expressions may arise from deficits in a motivation to express positive emotions with others. The difficulties may also stem from physiological problems in physically creating expressions that are due to damage to areas of the brain that control the facial nerve (which produces those expressions).
This project will utilize automated facial analysis software to compare how, when, and to what extent 20 four- to six year-old children with autistic disorder, 20 children with developmental disabilities, and 20 typically developing children produce facial expressions. Children will be observed playing social games with a tester and in a non-interactive context watching video clips and playing simple video games. These methods will provide insight in to the nature and possible source of the facial expressivity deficits expected in children with autism. If deficits are evident in an interaction setting but not when playing with video games, this would suggest deficits are related to an emotional motivation to engage. If deficits are apparent in both settings or are evenly distributed between positive, negative, and neutral expressive periods, this would suggest deficits are due to a physiological deficit.
What this means for people with autism: Discerning the probable source of difficulties in facial expressivity will provide a more complete understanding of social deficits in autism and suggest therapeutic approaches that are most appropriate for children with autism.
Cynthia Molloy, M.D.
Cincinnati Children's Hospital Medical Center
$449,742 for 3 years
Genome-wide Association Study of Autism Characterized by Developmental Regression
By some estimates, up to 30% of children with autism experienced developmental regression characterized by the acquisition and subsequent loss of social and communication skills. Dr. Molloy plans to explore the genetic component of this devastating phenomenon by analyzing and comparing the genetic “profile” of children with autism affected by regression with normally developing counterparts. By focusing on a more homogenous subset of the population, she and her colleagues hope to identify autism susceptibility genes, especially those that might be related to regression.
What this means for people with autism: If the subset of children who are likely to experience regression can be identified genetically, it could provide biomarkers for earlier diagnosis and aid in the development of intervention strategy related to those gene changes.
P. Read Montague, Ph.D.
Baylor College of Medicine
$450,000 for 3 years
Neural Correlates of Social Exchange and Valuation in Autism
Recent advances in brain imaging techniques mean that it is now possible to examine how the brain is functioning when an individual carries out a social ‘task' or exchange. Hyperscan functional magnetic resonance imaging (h-fMRI) i.e. the simultaneous measurement of brain activity in two socially interacting people, is an important development for autism research. The present study aims to combine computational approaches with functional brain imaging to examine how the neural systems involved in social interactions go awry to yield the social deficits seen in autism spectrum disorders.
Specifically, a social exchange task called an iterated Trust game and h-fMRI will be used to characterize neural and behavioral responses to social signals in individuals with autism as they participate in dynamic social exchanges with a human partner. The study will also use a ‘computer partner' to examine differences in the sensitivity of individuals with autism spectrum disorder to signals of social reciprocity - the computer partner will be made to vary its responses from ‘human-like and socially responsive' to ‘random and not socially-responsive'.
What this means to people with autism: The proposed work promises not only to contribute to the current understanding of the neural substrates of autism and its social sequelae but to provide a technological way to define new phenotypes and ultimately identify specific subtypes of autism spectrum disorders. This could inform the design, target, and implementation of new diagnostic and intervention protocols.
Glenn Rall, Ph.D.
The Fox Chase Cancer Center
$273,782 for 2 years
Consequences of Maternal Antigen Exposure on Offspring Immunity: An Animal Model of Vertical Tolerance
How pathogens and/or altered immune responses to pathogens or vaccines are related to the etiology of childhood autism remains unresolved. Recently, a chronic neuroinflammatory response was reported in some children with autism. In separate mouse studies, it was shown that maternal exposure to viral pathogens during pregnancy could adversely influence neurodevelopment in her offspring. Whether these findings are linked, and how they relate to the onset of autism, remain unresolved.
The goal of this pilot project is to perform basic science experiments in a mouse model of central nervous system infection with measles virus (MV) to explore the potential link between maternal immune history and neuroinflammation. In preliminary experiments, Dr. Rall has shown that neonatal mice born of mothers that were previously infected with MV had increased expression of pro-inflammatory molecules, including those observed in autistic children. Moreover, the neonates appeared to be immunological tolerant to further infection by MV. This project will further characterize these findings in greater detail to gain insight into the impact of human maternal immunity on the developing immune system of her progeny.
What this means for people with autism: This project will help define the role that altered immunity and chronic neuroinflammation play in the etiology of autism spectrum disorders.
Vijaya Ramesh, Ph.D.
Massachusetts General Hospital
$449,988 for 3 years
Role of Pam in Synaptic Morphology and Function
The co-occurrence of Autism Spectrum Disorders (ASD) and Tuberous Sclerosis Complex (TSC) has been recognized for many years. Features of ASD are present in 25-50% of individuals with TSC, a neurodevelopmental disorder caused by mutations in tumor suppressor genes TSC1 and TSC2, encoding hamartin and tuberin respectively. Tuberin and hamartin function together to inhibit mTOR signaling, which regulates protein synthesis and cell growth. In addition to being a critical regulator of cell growth, mTOR signaling plays an essential role in neural plasticity and synapse function by modulating local protein synthesis in neurons. Dr. Ramesh has identified another protein, Pam (Protein Associated with Myc), that interacts with the TSC2 protein tuberin and modulates mTOR as well.
The central hypothesis of this proposal is that Pam functions as an E3 ubiquitin ligase and controls the balance of synaptic proteins. The synapse, a basic unit of function in the nervous system is the primary site of communication between neurons. Aberrant expression of Pam could perturb this balance resulting in excess or reduced neuronal connectivity. Mutations in another E3 ligase have been reported in autism associated with Angelman's syndrome. These observations, as well as the link between TSC and autism, strongly support the hypothesis that Pam could be a potential player in ASD.
What this means to people with autism: This project is devoted to understanding the role of Pam in mammalian synapses as well as generating an animal model to serve as a valuable model for understanding how synaptic activity may be regulated in ASD.
James Rand, Ph.D.
Oklahoma Medical Research Foundation
$450,000 for 3 years
Role of Neuroligin in Synapse Stability
One of the most important results emerging from the intensive international effort to identify "autism-related" genes has been the demonstration of an association with autism (in some families) of mutations in genes encoding a family of proteins called neuroligins. Neuroligins are synaptic proteins present on post-synaptic cell membranes, and they bind specifically to a set of presynaptic membrane proteins called neurexins. Studies have shown that the binding of neuroligin to neurexin can be sufficient to mediate the assembly of the presynaptic components of a synapse. Mutations disrupting the NLGN3 and NLGN4 genes seem to be associated with autism. The association of autism with a disruption in components involved in synapse structure provides a point of entry for investigating the altered development and "miswiring" of the brain in autistic individuals.
This proposal will analyze the molecular genetics and cell biology of neuroligin and its role in synapse maintenance in the nematode C. elegans. Using this simple model system, the researchers will be addressing basic issues about the function of neuroligin in the development of the nervous system. Specifically they will study how synapses are impacted by the absence of neuroligin, what other molecules function with neuroligin to regulate synapse stability, and whether adding back neuroligin to the adult organism can rescue the abnormal development which occurred in its absence.
What this means for people with autism: Understanding the function of neuroligin in better detail will reveal the molecular pathways that are disrupted in autism and provide the information needed to design strategies to remediate the biological underpinnings of autism.
Donald Rojas, Ph.D.
University Of Colorado Health Sciences Center
$184,089 for 3 years
Gamma band dysfunction as a local neuronal connectivity endophenotype in autism
It has been proposed that general abnormalities in structural and functional neuronal connectivity may underlie many of the triad of deficits observed in autism. For example, weak central coherence and abnormal temporal binding may be related to alterations in brain functional and/or structural connectivity. Gamma band oscillatory activity, as measured using EEG and magnetoencephalography (MEG), is thought to play an important role in binding and central coherence. Some experiments have demonstrated that gamma activity is abnormal in people with autism, possibly reflecting a cortical GABA dysfunction.
Using a whole-head MEG system, the investigators will study activity within the auditory cortex and estimate patterns of cortical synchronization and desynchronization with high precision in both time and frequency. In order to uncover new endophenotypes for autism and the broader spectrum, the researchers will also study parents of affected individuals. Parents of children with autism will be assessed using MEG measures of gamma-band activity in motor and auditory tasks. Their data will be compared to matched adults with no family history of autism spectrum disorders and to matched adults with autism. MEG measures of gamma power and phase-locking will be measured and associated with their structural underpinnings from magnetic resonance imaging (MRI) data.
What this means for people with autism: This project will search for broad patterns of abnormal brain activity in individuals with autism and their family members, which may lead to new ways of diagnosing the disorder.
Erik Ullian, Ph.D.
University of California, San Francisco
$449,344 for 3 years
Role of Micro-RNAs in ASD Affected Circuit Formation and Function
Fragile X syndrome is a common disorder with clear relevance to autism spectrum disorders (ASD). Recently, it was discovered that the protein underlying this syndrome, FMRP, plays important regulatory roles in neuronal translation of RNA into protein. This discovery has opened up tremendous opportunity to study related mechanisms that are likely to be associated with autism. One common, but poorly understood, mechanism of translational control involves endogenous small RNAs. Small RNAs, including microRNAs (miRNAs) are expressed during development and through adulthood and it is clear that they play important regulatory roles in neuronal function. The greatest variety of miRNAs are expressed in the nervous system, including the cortex and cerebellum, making it paramount to understand what role miRNAs play in normal neuronal function and disease.
To date only two miRNA has been investigated in hippocampal neurons in vitro and these miRNA were found to regulate process outgrowth and synapse formation. Importantly, computational analyses of likely targets of their action indicate that numerous signaling pathways impacting neuronal function are regulated by miRNAs. Because cortical pyramidal and cerebellar Purkinje neurons are consistently affected in ASD, this project will use the power of mouse genetics to initially remove all miRNAs from cortical circuits and cerebellar Purkinje neurons after they have developed and ask what role miRNAs play in neuron survival, synaptic connectivity, and function.
What this means for people with autism: This project investigates the potential involvement in autism of a newly discovered pathway that regulates brain function. By focusing on the molecular mechanisms of the disorder, targeted therapeutic strategies for intervention can be developed.
Flora Vaccarino, M.D.
Yale University
$446,744 for 3 years
Neurogenic Growth Factor in Autism
In addition to their prominent role in certain types of cancer, genes in the fibroblast growth factor (FGF) pathway have been shown in animal models to be important for brain development. Animals with mutations in FGF genes, for instance, exhibit anatomical characteristics reminiscent of those observed in autism. Dr. Vaccarino plans to interrogate these genes for variants associated with autism. Using samples she collected as well as those from AGRE, she also plans to correlate changes in these genes associated with autism with changes in brain size and structures.
What this means for people with autism: If FGF genes are confirmed as genetic risk factors, autism research could benefit greatly from a wealth of information already available from a well characterized disease-causing mechanism, which could speed the development of targeted therapeutics.
Fred Volkmar, M.D.
Yale Child Study Center
$450,000 for 3 years
A Randomized Controlled Trial of Two Treatments for Verbal Communication
This study will examine the relative effectiveness of two communication interventions on the production of speech in 40 preschool children with ASD (3 to 6 years) who are pre-linguistic i.e. produce fewer than 10 different words. The two experimental treatments will be added to whatever interventions the child is receiving the community. The primary aim is to assess the effectiveness of a direct speech-focused treatment versus a naturalistic approach on the production of speech and the adaptive use of verbal communication. The study will also determine the effect of a parent-delivered generalization program on the maintenance of gains of the interventions provided.
The two treatments that will be compared are a direct speech-focused treatment, the Rapid Motor Imitation Training, that reinforces motor imitation (and later targets verbal requests and labels) versus a naturalistic approach the Prelinguistic Milieu Teaching (PMT), which has been demonstrated to be effective in increasing communicative behavior in young children with various developmental disabilities. At the end of the treatment period, the children will be assessed by the number of spoken words and expressive communication level. Further, in an effort to match child traits to the most appropriate treatment approach, the data will be analyzed to determine which child characteristics prior to the intervention are associated with greater gains in either of the two treatments.
What this means for people with autism: This project aims to compare the effectiveness of two established behavioral treatments aimed at improving language and communication abilities in preverbal, preschool children with ASD. It will advance evidence-based practice in the early intervention arena. It will also supply useful information for predicting the best treatment method to use with children who have particular profiles of prelinguistic development, so as to provide the most effective match between child and intervention.
Harland Winter, M.D.
Harvard Medical School
$450,000 for 3 years
Identifying Gastrointestinal (GI) Conditions in Children with Autism Spectrum Disorders (ASD)
Gastrointestinal (GI) dysfunction is relatively prevalent in children with ASD, but is especially difficult to diagnose, not only because of the social and communication deficits which prevent effective reporting of symptoms, but also the difficulties clinicians face in correlating behavior with specific GI disorders. Current clinical practice guidelines include neither routine GI evaluation nor diagnostic criteria or protocols that consider the special gastrointestinal needs of this patient population.
Therefore, the first objective of the proposed study is to develop and validate effective and appropriate diagnostic screening methods to detect symptomatic GI dysfunction in children with ASD. The second objective of the proposed research is to determine whether gastrointestinal (GI) dysfunction contributes substantially to the expression of problem behaviors (PB) in children with ASD and to determine, if specific behaviors, including but not limited to PB, are increased in those children with gastrointestinal dysfunctions. The main hypothesis to be tested is that painful or discomfort-causing gastrointestinal (GI) dysfunction occurs frequently in children with ASD, and contributes to an elevated incidence or severity of PB in an identifiable subpopulation of these children.
What this means for people with autism: The results of the study will inform the medical community about the prevalence of GI symtpoms as they relate to autism and will provide evidence that will inform clinical practice guidelines for children with ASD, thereby improving quality of life for these young patients and their family members.
Anthony Zador, M.D., Ph.D.
Cold Spring Harbor Laboratory
$450,000 for 3 years
Analysis of Cortical Circuits Related to ASD Gene Candidates
Although autism is among the most heritable of the common neuropsychiatric disorders, it is increasingly clear that no single gene mutation is responsible for all or even most cases. A growing number of genes have been implicated in the etiology of autism, but the candidate genes form a very heterogeneous collection. What do these genes have in common? What is the “final common pathway” that leads to autism? We hypothesize that this heterogeneous collection of autism gene candidates leads to dysfunction at the level of neural circuitry that is more homogeneous and thus easier to understand.
This project aims to develop an efficient way of studying, in rodents, the deficits in neural circuitry resulting from the perturbation of autism candidate genes. The investigators will disrupt the function of candidate autism genes and use a combination of in vitro and in vivo technologies to probe for circuit level effects. They will use this strategy to test a leading hypothesis about the circuit dysfunction underlying autism, namely that autism results in a functional imbalance between excitatory and inhibitory synaptic activity. Rat auditory cortex will be used as a model system. Sensory abnormalities, particularly in the auditory domain, are one of the characteristic signs of autism. The initial focus will be on the neuroligins, a candidate gene family implicated in autism. In summary, this project proposes to develop a general and efficient strategy for relating genetic and physiological dysfunction in rodent models of autism.
What this means for people with autism: Although the causes of autism may be many, understanding the circuit effects of autism genes will lead to a better understanding of how treatments can be designed to target the common biological mechanisms underlying autism.
back to top
|
|
|
|
|
|
|
|
||||||
