REGULATION OF NEUROTRANSMISSION AND BEHAVIOR

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DESCRIPTION: (applicant's abstract) Proper function of the nervous system requires the development and maintenance of appropriate neuronal connectivity and effective communication that is largely mediated by chemical synapses. Deficits in synaptic connectivity, resulting from genetic or epigenetic abnormalities revealed either during development or after acute pharmacological or environmental insult, are likely to contribute significantly to impaired brain function. Regulated exocytosis of classical neurotransmitters, as well as neuropeptides and modulatory neurotrophic factors is proposed to underlie the necessary presynaptic input for effective communication between neurons. The overall goal of the research of this laboratory is to gain a better understanding of the molecular mechanisms which control neuroexocytosis. Moreover, implicit in these studies is the general hypothesis that presynaptic regulation of neurotransmitter release can modulate brain development and function, and consequently that deficiencies in this molecular machinery can play at least a part in the cognitive and behavioral impairments of neuropsychiatric disorders. To address these issues, we have focused on the protein SNAP-25, which we propose plays a regulatory role, as well as its more well-defined part as an integral structural component of the exocytotic protein machinery necessary for vesicle fusion and neurotransmitter release. Our investigations make use of SNAP-25 null and hypomorphic mouse mutants which we have developed in the previous funding of this grant. In Specific Aim 1 experiments are designed to use Snap25-/- mice to determine the role of neuroexocytosis in axon stabilization and synapse formation. Specific Aim 2 will use replication defective viral expression systems and Snap25-/- cultured neurons to examine role of sequences that are postranslationally modified and distinguish developmentally regulated SNAP-25 isoforms. Specific Aim 3 addresses the hypothesis of whether the developmental switch in SNAP-25 isoforms underlines the maturation of synaptic transmission by electrophysiological and neurochemical measurements of SNAP-25b hypomorph mutants. Finally in Specific Aim 4, experiments are designed to examine whether Snap25 heterozygotes that express reduced levels of SNAP-25 are more susceptible to psychotomimetic drugs and thus are a model of genetic vulnerability. If successful this investigation will shed light on the selective roles of SNAP-25 isoforms, the roles they play in the synaptic plasticity required for normal brain function, and how abnormalities in presynaptic mechanisms of neurotransmission may be involved in neuropsychiatric disease.