[unreadable] The development, maintenance and control of neurotransmitter secretion at chemical synapses underlie the neuronal communication necessary for the proper function of the nervous system. Deficits in synaptic transmission and connectivity, resulting from genetic or epigenetic abnormalities revealed during development, are likely to contribute to impaired brain function. In particular, regulated exocytosis of classical neurotransmitters and neuropeptides is a key factor that underlies the necessary presynaptic input for effective communication between neurons. The overall goal of the research of our laboratory is to gain a better understanding of the molecular, cellular and developmental mechanisms which control neuroexocytosis. Our hypothesis is that the developmental regulation of the composition of the molecular machinery responsible for membrane trafficking and vesicular fusion for neurotransmission is instrumental in developing how neurons communicate during the initial contact and formation of synapses, and ultimately in sculpting the synaptic physiology of the mature nervous system. To address this hypothesis, we have focused on the protein SNAP-25, a key element of the SNARE complex mediating membrane fusion for transmitter release. We propose that the transition from a constitutively expressed homologue, SNAP-23, to the regulated expression of SNAP-25 isoforms plays a key role in mediating vesicle fusion for growing axons to functional synapses capable of evoked neurotransmitter release and synaptic activity. Our investigations make use of Snap25 gene mutants in the mouse developed through previous funding of this grant and a conditional mutation to be generated during the present period. In Specific Aim 1, experiments are designed to examine the role of spontaneous neurotransmitter release in cultured cells and fetal brain development using Snap25 null mutants. In Specific Aim 2, we will examine whether the switch in SNAP-25 isoforms is required for maturation of synaptic transmission during postnatal development using a mutation that prolongs overexpression of the SNAP-25a isoform. Finally in Specific Aim 3, we will extend our analysis to study later steps of synaptogenesis and synaptic maturation that occur after birth, and in the long-term neurodegenerative processes, by investigating synaptic functions of a conditional Snap25 gene mutation controlled by inducible expression of Cre recombinase. If successful, these investigations will shed light on the roles of SNAP-25 and its isoforms during development and for synaptic plasticity required for normal brain function, and how abnormalities in presynaptic mechanisms of neurotransmission are involved in neuropsychiatric disease. [unreadable] [unreadable]
NIH ExPorter
NIH ExPorter