Autism Spectrum Disorder (ASD) is a developmental disorder characterized by inappropriate responses to social and sensory stimulation, restricted communication, and stereotyped behavior. Heterozygous mutations in the gene Pten (phosphatase and tensin homolog on chromosome 10) have been identified in 5 to 17% of patients presenting with autism and macrocephaly. Further, experimental deletion of Pten in the mouse brain also causes macrocephaly and deficits in social behavior, suggesting a causative role for Pten dysfunction in the development of ASD. At the cellular level, Pten knockdown results in aberrant growth and increased excitatory synaptic function. Thus, study of Pten fits perfectly with our long-term goal of understanding how synaptic connectivity and activity contribute to complicated cognitive and emotional functions. Our central hypothesis is that Pten dysfunction in autism patients results in aberrant excitation of susceptible neural circuits. Guided by this hypothesis, the specific aims of this proposal will strengthen our understanding of the molecular and neurophysiological basis of ASD. Manipulation of Pten in vivo presents a unique opportunity to examine the neurophysiological basis of autism in a model organism.
Our first aim will test the hypothesis that Pten knockdown results in hyperexcitability of a defined circuit. The symptoms of autism are often most severe during development, and decrease in severity during adolescence and adulthood. Identification of endogenous mechanisms by which the adult brain becomes more resistant to genetic insults causing autism could lead to new treatments.
Our second aim will test the hypothesis that developing neurons are intrinsically more sensitive to the effects of Pten knockdown. A key gap in our understanding of how Pten contributes to autism exists because we have not examined whether Pten point mutations are equivalent to knockdown. Examining point mutations found in patients will serve as a starting point to identify intra- and intermolecular interactions of Pten relevant to the autism phenotype. For the third aim, we will test the hypothesis that point mutations identified in patients will reslt in cellular phenotypes relevant to the autism model. This proposal will use the innovative approaches of viral-based knockdown and molecular substitution in vivo, coupled with detailed morphological and electrophysiological analyses. The broad goal of this research is to define the molecular and physiological basis of how Pten dysfunction contributes to some forms of autism.

Public Health Relevance

This research proposal is relevant to public health because it addresses issues related to the molecular pathophysiology of autism spectrum disorder. Thus it is directly relevant to the part of NIH's mission outlined in PA-10-158 - Research on Autism and Autism Spectrum Disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Panchision, David M
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Dartmouth College
Schools of Medicine
United States
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