This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Deficits in GABAergic transmission predispose people to epilepsy and mental retardation. This project seeks to determine contributions of inhibitory mechanisms to the developmental aberrations in the cerebral cortex. Genetics and ?epigenetic? influences might interfere with the normal program of brain development and give rise to aberrant patterns of cortical structure and patho-psychosis states. The proposed research will focus on developmental maladaptive reorganization of gamma-aminobutyric acid (GABA) and glycine transmission and their contribution to epileptiform activities in the sensory motor cortex. It will be determined: (1) if neocortical malformation leads to maladaptive reorganization of local inhibitory connections and mechanisms underlying the hyper-excitable state in the malformed cortex. (2) if during a developmental critical period, GABA neurotransmission is necessary to support synaptic plasticity and normal maturation of sensory-specific cortical circuits. Confocal microscopy, whole-cell patch clamp recording, immunocytochemistry, genetic knock-out/knock-in manipulation, and electron microscopy will be used to test the hypothesis that: balanced excitation and inhibition are critical for the formation of the normal functional sensorymotor cortex and that maladaptive reorganization of inhibitory transmission plays a permissive role for epileptogenesis and sensorymotor deficit. The studies proposed here will generate further understanding about how developing inhibitory brain circuits adapt to insults and loss balance with excitatory circuits and will provide new information about mechanisms of neocortical malformation, epilepsy and mental retardation.
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