Autism is a severe neurodevelopmental disorder with genetic and environmental etiologies and a prevalence rate of 16 per 10,000, which appears to result from altered development of nervous tissue pre- and postnatally. The central hypothesis of this application is that certain gene families involved in cell growth and migration and GABAergic neurotransmission will be altered in autism. This central hypothesis will be tested and the objectives of this application accomplished by pursuing two Specific Aims: 1) Determine the mRNA and protein levels for Reelin, its receptors, and downstream molecules in the Reelin signaling system in cerebellar, hippocampal, and frontal cortices of autistic subjects and matched controls;and 2) Determine the mRNA and protein levels for GAD 65 and 67 kDa proteins and GABA receptors in cerebellar, hippocampal, and frontal cortices of autistic subjects and matched controls. We will employ previously established qRTPCR, SDS-PAGE and western blotting, and in situ hybridization techniques to quantify various mRNA and protein species. It is our expectation that we will demonstrate gene and protein alterations in brains of autistics involving GABAergic markers, Reelin and its downstream components, linking GABAergic dysfunction to autistic brain structural abnormalities. Such outcomes will be significant, because they are expected to identify biochemical mechanisms responsible for abnormal brain development in early childhood, as seen in autism.
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