GABAERGIC NEUROPHYSIOLOGY IN AUTISM SPECTRUM DISORDER. The GABAergic system has been found to be important in the pathophysiology of autism spectrum disorder (ASD), as evidenced by postmortem studies and animal models of ASD. The overall objective of this application, which is a critical step toward attainment of my long-term goal, is to use a cutting-edge methodology in assessing the GABAergic system in living human beings with ASD. We hypothesize that the GABAergic tone is lower in the thalamocortical network in the brains of individuals with ASD, compared to neurotypical controls. We further postulate that GABAA receptor densities and GABA levels in the DLPFC (or thalamus) will have an interactive effect on social-communicative abilities.
The Specific Aims of this proposal are to: (1) characterize the distribution of GABAA receptors in adults with ASD; (2) determine the abnormalities in GABA levels in thalamocortical networks in adults with ASD; and (3) examine the independent and interactive effects of GABAA receptor densities and GABA levels in the thalamus and DLPFC, on socio- communicative abilities. This 4-year program will involve training in specific neuroimaging methodologies, as well as general research and ethics. Imaging methods used in this proposal will be positron emission tomography (PET), magnetic resonance spectroscopy (MRS), and structural magnetic resonance imaging (sMRI). Antonio Hardan, M.D. (Director of Autism & Developmental Disabilities Clinic, Department of Psychiatry & Behavioral Sciences, Stanford University) and Greg Zaharchuk, M.D., Ph.D. (Associate Professor, Department of Radiology, Stanford University) will co-mentor the principal investigator's scientific development. Both Dr. Hardan and Dr. Zaharchuk have substantial experience in various areas of neuroimaging and in the application of related research methods, as well as experience training postdoctoral fellows and NIH grant recipients. The proposal is also supported by a rich diversity of collaborators and consultants to provide education and guidance in various aspects of research (PET in individuals with ASD, MRS, and biostatistics). The principal investigator has completed residency training in Psychiatry, fellowship training in Child & Adolescent Psychiatry, and a Post-doctoral research fellowship at Stanford University School of Medicine. He also holds advanced degrees in Chemical Engineering, and has industry experience in pharmaceutical discovery and development.
In current clinical practice, diagnosis of autism spectrum disorder (ASD) is performed by identification of behavioral and cognitive symptoms, and treatments for ASD are completely empirical. Identification of specific molecular abnormalities (related to a the major inhibitory neurotransmitter GABA) in targeted brain networks, as is proposed, would allow for better assessments of abnormalities of brain circuits associated with the cognitive-behavioral deficits, and more rational and effective development of interventions that are based on molecular abnormalities in specific brain networks. Therefore, the proposed work in molecular neuroimaging in individuals with ASD will help the field to depart from the symptom-clustering approach in diagnosis and empirical approach in treatments, and move toward more mechanism- and biomarker-based diagnostic and intervention strategies. !