Catalina Betancur, M.D., Ph.D., INSERM France (Young Investigator)
Recently an international collaborative project, the Paris Autism Research International Sib-pair (PARIS) study, performed a genome-wide screen for susceptibility genes in 51 multiplex pedigrees affected with autism. Among the 12 potential chromosomal regions identified, five overlapped with results of other recent studies. This project will focus on these five regions in the sib-pair population and in an additional population of trios (affected child and both parents) in order to lead to greater understanding of the etiology and pathogenesis of autistic disorders. First year funding partner: Eugene and Sherna Schloss in honor of their grandson, Samuel Mathias Schloss
Hudson H. Freeze, Ph.D., The Burnham Institute (Pilot Research)
Glycosylation (the process of adding sugar chains to proteins) occurs in all proteins in the blood and many in the cell membranes. Much of the cell-cell communication during embryonic development also involves glycosylation. As a result, it has many roles in the body including control of how proteins fold into their active shapes or their delivery to the proper location inside the cell, and movement of white blood cells during infections or inflammation. This means that the loss of a sugar chain or construction of an incomplete sugar chain can have many serious consequences. Several patients with an unknown glycosylation defect have show to have an autistic-like presentation. This study with focus on locating their defect as well as screening multiplex families for signs of altered glycosylation.
Daniel Goldowitz, Ph.D., University of Tennessee, Memphis (Pilot Research)
Using a neurogentic mouse model of autism that is being developed, this project will combine experimental embryological, behavioral and anatomical techniques to explore the role of perturbations of the cerebellum in the onset of behaviors that mimic autism. This model can then be used to test interventions during development aimed at improving and eliminating behavioral deficits.
Eric R. Kandel, M.D., Columbia University (Bridge Grant)
This group is interested in developing an animal model for components of autism. Accumulated evidence from previous studies suggests that emotional state in autistic patients, disorders of anxiety and depression, and experimental models like Kluver-Bucy syndrome have in common one structure in the brain, namely the amygdala, which deals with unconscious memories of emotions and fear. Therefore the localization, cloning and further characterization of the genetic substrates underlying amygdala function and its relationship to autistic behavior will allow for a detailed molecular analysis of the anatomical and signaling pathways that contribute to the clinical syndrome.
Laura B. Kubicek Herzing, Ph.D., University of Chicago (Young Investigator)
Human chromosome 15 (15q11-13) contains hotspots for chromosomal rearrangements, flanking a variety of genes involved in brain development and function. These include candidate loci for schizophrenia (CHRNa7) and Angelman Syndrome (UBE3A), as well as GABA, receptor subunit genes. UBE3A is, in mice, imprinted in regions of the brain which may show abnormalities in autism, and transgenic mice deleted for GABRB3 demonstrate potential autistic features. Intriguingly, maternal inheritance of a duplicated 15q11-13 region is associated with autism, and autism/PDD/atypical AS are also observed with presence of a supernumerary marker chromosome derived from this region. In addition, linkage to 15q11-13 has recently been detected in non-dup(15) autism patients. Together, these observations strongly suggest 15q11-13 contains an autism gene(s). The primary ways in which alteration of gene/region copy number could influence phenotype involve changes in gene expression levels. To analyze gene expression across 15q11-13, and to determine a possible correlation between gene expression patterns and autism, I will utilize Reverse-Transcriptase-Polymerase-Chain-Reaction and RNA-Fluorescence In-Situ Hybridization. The imprint status will be determined for genes across the region, primarily in the brain; maternal-specific expression could explain the correlation between maternal inheritance of dup(15) and disease phenotype. Expression levels of genes between dup(15) (autism), marker(15), karyotypically normal autistic patients and normal controls will be compared to determine over/under expression of gene clusters/chromosome regions and individuals genes. This data will help identify candidate genes for autism, provide valuable information for other neurobiological genes in the region, and may be instrumental in determining a mechanism for the dup(15) phenotype.
Ludise Malkova, Ph.D., Georgetown University Medical Center (Pilot Research)
A primary symptom of autism is impairment in social relations. This impairment together with mental retardation suggests, based on human cases and experiments in nonhuman primates, that dysfunction in medial temporal lobes might be involved in the etiology of this developmental disorder. Our previous studies have shown that early damage to the medial temporal lobes (including the amygdala) in monkeys resulted in severe and long-lasting socioemotional disturbances, such as the dramatically reduced social contact and increased self-directed activities, strikingly similar to those seen in autistic children. These disturbances were more severe than those after the same lesions inflicted by the same lesions in adulthood and were related more specifically to the amygdala. Here, we are proposing an alternative approach to lesion studies, a transient pharmacological inactivation of the amygdala to more precisely investigate the neural substrates of social interactions in infant monkeys. Focal infusions of drugs that block glutamate transmission will be aimed at particular subdivisions of the amygdala in freely moving, nonsedated monkeys and the effects of these drugs on social interactions in monkeys observed in pairs (as differentiated from nonsocial cognitive task performance) will be assessed. If our aims are achieved, it will allow us to embark in the future on studies to evaluate the developmental impact of focal drug application in the monkey; an important goal will be to determine of a repeated blockage of the transmission in the amygdala over a critical period of the monkeys' developmental results in long-lasting consequences for its socioemotional behavior.
Stephen W. Porges, Ph.D., University of Maryland (Pilot Research)
This study hypothesizes that social interaction and communication problems for many autistic children are, in part, caused by functional problems and not irreversible structural problems in the nervous system. Thus, to promote more appropriate social behavior, an intervention has been designed which attempts to stimulate and exercise the cortical regulation of the nerves that control the muscles in the head through computer-altered acoustic stimulation delivered via earphones in a quiet, supportive environment. Preliminary results show positive improvements immediately following intervention and persisting during a three month follow-up.
Isabelle Rapin, M.D., Albert Einstein College of Medicine (Pilot Research)
Studies show that a great majority of toddlers who undergo a language regression develop autistic behaviors that usually persist. In fact, language/behavioral regression is reported by at least a third of parents of children on the autistic spectrum. The cause of the regression is unknown because children are rarely referred at the time of the regression. The purpose of this study is to determine whether subclinical epilepsy (which is diagnosed when a prolonged sleep EEG shows epileptiform activity even though the child has no known seizures) plays a role in early language regression. Progress of children who receive medication will be compared with those who do not but, like the others, are receiving speech/language therapy and special education at home or in school. Children will be followed at three and six months to determine the course of their language and behavioral deficits. Pilot data provided by this study will be used as the basis for submission of an NIH grant for a large 4 arm multi-institutional double blind treatment trial.
Lizabeth M. Romanski, Ph.D., Yale University (Young Investigator)
Research has shown that the ventrolateral frontal lobe is involved in both face perception and the processing of language related sounds. This convergence of face and language information on a single region of the frontal lobe suggests that this brain region may be important for memory, communication and social interaction, and thus may be particularly affected by autism. This project is aimed at further understanding how the neurons and brain circuits in this region normally participate in face and language processing. This may help to develop better and earlier diagnostic tests and design targeted treatments aimed at improving language and social capabilities in children with autism.
Richard Shubin, M.D., Huntington Memorial Hospital (Bridge Grant)
Although parents of children with autism have long known that their children have significant problems with sleep, there is a dearth of scientific and medical literature on the impact of sleep disorders on the lives of these children. A systematic effort to improve nighttime sleep by diagnosing and treating sleep disorders could enhance the ability of the child to function during the day. We will study sleep in autistic children using polysomnography in a clinical context.