Synapse formation is critical for the initial wiring of the central nervous system. Improper formation or function of these synapses underlies many neurodevelopmental disorders such as mental retardation, autism, and possibly even schizophrenia. One of the initial events in the formation of a glutamatergic synapse is accumulation of mobile synaptic vesicle precursors (STVs)3 at nascent synapses within minutes of initial axodendritic contact 4. These STVs are mobile transport packets that transport many proteins associated with synaptic vesicle cycling. STVs are transported in both directions along the axon, cycle with neuronal membrane, and frequently pause during transport. Although the mechanisms of this transport must be modified to allow for accumulation at nascent synapses, little is known about how STV transport is regulated. Perhaps the most attractive candidate molecule for regulating STV trafficking and accumulation at nascent synapses is the actin cytoskeleton. Actin is essential for synaptic vesicle trafficking at mature presynaptic terminals, F-actin accumulates at nascent synapses, and disruption of actin dynamics prevents the formation and maintenance of new hippocampal synapses. The central goal of this proposal is to investigate the role of actin dynamics in the regulation of transport and recruitment of STVs to new synapses between visual cortical neurons. To this end, we will address three specific aims. (1) We will test the hypothesis that actin regulates STV trafficking before synapse formation. (2) We will test the hypothesis that actin regulates STV accumulation at nascent glutamatergic synapses. (3) We will test the hypothesis that Rho GTPases mediate the effects of actin on STV trafficking before and during glutamatergic synaptogenesis.
These specific aims are designed to elucidate the molecular mechanisms that underlie glutamatergic synapse formation in the mammalian central nervous system, and more generally, grant insight into the causes of neurodevelopmental disorders where synapse formation is altered. ? ?
