2000 Grants Funded (CAN)

Conditional neurotrophin knock-out mice as a model for the developmental neuropathology of autism

Schahram Akbarian, Ph.D., Massachusetts General Hospital (Young Investigator)
Dr. Akbarian's group has recently generated a mutant mouse that lacks the developing brain neurotrophin-3 (NT-3), a growth factor molecule. The mice are viable and have a normal life span. However, their brains have some developmental abnormalities that, interestingly enough, have also been found in some cases of autism. These include abnormal shape and size of the cerebellum (a brain structure in the back of the brain involved in motor control and thought processing) and abnormalities in the prefrontal and cingulate cortex (a brain area that is important for emotion, social interaction and thought processing). It is possible that a mouse that lacks NT-3 in the developing brain may become one of the first animal models for autism. This project's goal is to clarify this hypothesis. An animal model of autism will be of great advantage for autism research, because it would allow for the testing of novel drugs as a potential treatment for autism.

Sensory-motor and social-communicative symptoms of autism in infancy

Grace T. Baranek, Ph.D., University of North Carolina, Chapel Hill (Pilot Research)
Defining the diagnostic symptoms of autism in infancy and understanding the early course of development for infants with autism are essential components of the effort to find effective treatments and possible cures for this neurodevelopment disorder. The conventional diagnostic criteria that are appropriate for somewhat older children with autism cannot be applied to the screening or diagnosis of infants for autism due to their reliance on judgments about behaviors that do not typically emerge until developmental ages beyond infancy. Some early social-communicative behaviors such as pointing at objects to show them to others have proven useful in screening for autism at 18-24 months of age, based on work by Simon Baron-Cohen and his colleagues in England. In addition, recent work by the principal investigator of this project suggests that the sensory-motor behaviors of infants with autism differ from both infants developing typically as with an infants with other developmental disabilities as early as 9-12 months of age. For example, infants with autism mouthed objects excessively, responded less to novelty in the environment, showed more aversion to touch, and were less responsive to people calling their names as compared with other infants.

Three-dimensional morphometry of the hippocampus in children with autism

Stephen R. Dager, M.D., University of Washington (Pilot Research)
The co-investigators on this project have extensive experience applying 3-D morphometric methods to the adult brain and have undertaken pilot work developing electronic templates of 3-year-old healthy controls. This project will be undertaken as a new research focus for their group, which has no previous experience investigating autism. Dr. Geraldine Dawson is nationally recognized as an expert on autism and will provide expertise on neurodevelopmental aspects of autism to ensure this technique-driven project retains a clinical ground. A "Neuroimaging of Autism" grant funded through NICHD, has been the entree into the field of autism research for the neuroimaging group at the University of Washington. To date, they have performed MRI/spectroscopy studies on 28 3-year-old children with autism. This grant proposal will allow the investigators to apply high dimensional imaging analysis tools that they have developed to systematically map out the 3-D morphometry of children's hippocampal region. This process will generate data comparing autistic children with age-related controls at ages 3 to 4 years and again at ages 6 to 7 years when restudied.

A non-human primate model to study prefrontal cortex dysfunction in autism

Stefan Everling, Ph.D., University of Western Ontario, Canada (Pilot Research)
A major problem in the search for the neural basis of autism is that many of the core symptoms like social isolation and language deficits are difficult or even impossible to investigate in animal models. Only recently, it has been discovered that autistic subjects have problems in a simple eye movement task. It was found that autistic subjects had no problems looking toward a spot of light, but it was very difficult for them to look away from the light. We believe that this finding can provide a new approach toward the investigation of the neural basis of autism, because eye movements can be investigated in monkeys. Monkeys and humans share all the brain areas that control eye movements and we already have a good understanding of the principal neural mechanisms that are necessary to move the eyes. This project will train monkeys on exactly the same eye movement task in which they see a spot of light and have to look the opposite way. The investigators will first identify the processes in the brain that occur when monkeys perform this task by recording the activity of single neurons in the brain. Then, the same behavior abnormality will be created in the animals that is found in the autistic subjects by deactivating and modulating the neural activity with substances that block the receptors of certain neurotransmitters that have been implicated in autism. This should provide insights into the brain mechanism that is altered in autism.

Identification of autism-linked genomic regions by a genome-wide mapping and genetic study of chromosomal abnormality of 15q

Jianjun Liu, Ph.D., Columbia University (Young Investigator)
Autism is a neuropsychiatric disease that occurs in 1 to 2 in 1000 children. Even though the physiological mechanism of autism is still not clear, scientific studies have shown that the development of autism is influenced by inheritable genetic factors. One of these genetic factors might locate in chromosome 15 because many cases have been reported indicating a possible association between the chromosomal abnormality of chromosome 15 and autism or autistic behavior. This project is proposed to further investigate this possible association in AGRE's families and, if the association is confirmed, to try to identify gene or genes that may increase the risk that a child will develop autism.

A review paper on secular trends in the occurrence of autism

Craig Newschaffer, Ph.D., Johns Hopkins School of Public Health (Contracted Research)
The goal of this project is to produce a research-review-style paper on trends in autism incidence of a quality suitable for publication in an academic journal. The paper will discuss available data (focusing on the most recent available information), explain epidemiological issues in the interpretation of such information, draw analogies from data on secular trends in the risk of a select set of other diseases initiating in early childhood, critically explore the coherence of the autism incidence data with current theories of autism causality, and make suggestions for research activities that would help improve our ability to accurately measure and interpret secular trends.

Identification of candidate genes for involvement in autism

Stephen W. Scherer, Ph.D., Hospital for Sick Children (Canada) (Pilot Research)
There is now overwhelming evidence of the importance of genetic factors in the etiology of autism. In fact, evidence points towards autism as being one of the neuropsychiatric disorders most influenced by genetic factors. Recent molecular genetic studies have found a region on human chromosome 7 that likely contains a gene which when mutated causes autism. Using cloning techniques, this project aims to identify this gene and develop a new research program in the molecular genetics of autism. The gene identification will provide insight into the basic molecular defect, allow for proper diagnosis and thoughtful family planning, and perhaps even lead to a treatment for autism.

Molecular mechanisms of Fragile X syndrome: Understanding the function of the drosophila homologue of the Fragile X gene, FMRI

Haruhiko Siomi, Ph.D., University of Tokushima (Japan) (Pilot Research)
Autistic features have been described in individuals with well-characterized genetic disorders, most notably fragile X syndrome. This suggests that there may be common mechanisms leading to the two disorders. Fragile X patients fail to make the protein product of the fragile X gene, fMR1. Animal models often provide us with great clues as to the mechanisms leading to given human genetic disorders. To elucidate the function of fMR1, we use the fruit fly as a model system since a plethora of new and old methodology is available that can be applied to questions involving complex behaviors such as learning and memory in fruit flies. Once we elucidate the function of the fruit fly fMR1, we can effectively begin to address the question of how the lack of fMR1 expression leads to symptoms including autistic features in fragile X syndrome.

Detection of autism and Asperger's syndrome in 4-10 month old infants

Philip Teitelbaum, Ph.D., University of Florida (Treatment Award)
This group is developing methods to facilitate the early diagnosis of autism and Asperger's syndrome, as early as four months of age. In 25 out of 25 infants so far, that turned out later to be autistic, the group has found characteristic disturbances in their movement that can be useful to diagnose them early. In Asperger's syndrome, the movements are less disintegrated than in more severe autism, but movement disturbances are present in every child studied by us so far. We want to produce a self-explanatory video that can be made available to parents, pediatricians, and professionals that will help them to recognize these movement disturbances so that they can refer the children for careful observation and therapy by professionals skilled in the treatment of autism and Asperger's syndrome. We are also investigating the lateral head-righting reflex as a simple rapid diagnostic screening technique useful for pediatricians to test for autism in babies as early as 8-10 months of age.