Neuropathological findings in autism have consistently implicated the hippocampus and amygdala, two key limbic system structures with specific but wide-ranging connections throughout many cortical regions. While the hippocampus has important functions in declarative and short term memory processes, the amygdala in contrast has been implicated in emotions, fear, anxiety and is critically important for social interaction with 3eers and the environment, in autism, individuals have difficulties with declarative memory and with socioemotional and affective behavior. Although the hippocampus and amygdala are the subject of many ongoing research studies, the direct and indirect cortical connectivity of these two key brain areas have not been well studied in autism. Thus, the present study will investigate six key cortical areas including two in the frontal lobe (medial and orbital frontal cortex), three areas in the cingulate gyrus (anterior and posterior cingulate and retrosplenial cortex) and the temporal lobe fusiform face area in the fusiform gyrus, each of which have important connections with either the hippocarnpus, amygdala or both. The hypothesis is that the circuitry within these limbic cortices is altered contributing to the social affective behavioral deficits in autism. The cellular structure and cortical cytoarchitecture will be studied via standard Nissl stains for cellular pathology in the six cortices. Since it now appears that abnormalities in benzodiazepine binding sites and GABA-A receptors have been identified in the hippocampus, the GABAergic will be investigated in the six cortical areas using a variety of methods. Immunocytochemistry will quantify subpopulations of cortical GABAergic intemeurons and assess the functional activity utilizing antibodies dierected against three types of GABAergic transporters (uptake sites). In addition, in vitro multiple concentration ligand binding will quantify the density of binding and affinity to bind benzodiazepine and GABA-A sites as well as three types of serotonergic receptors, another transmitter system implicated in autistic spectrum. Finally, the dynamic state within the brain of autistic individuals will be assessed utilizing antibodies toward two types of neuroglia: microglia and astrocytes. Microglial aggregations at sites of neuropathological changes wilt be a focus of the study with the hypothesis that autism is an ongoing process and not a static disorder.
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