This project addresses basic molecular and cell biological mechanisms of synapse formation in the mammalian central nervous system (CNS). This research will use novel optical imaging methods and a wide variety of molecular and physiological interventions to explore early stages of synaptogenesis in cultures of rat hippocampal neurons. The experiments we propose will address three sets of questions: 1. What cell motility and growth processes initiate physical cell-cell contact at specific sites of synapse assembly, and how are these motility mechanisms regulated? 2. What roles cell adhesion molecules (particularly members of the cadherin superfamily) play in sustaining synaptogenic contact and triggering synapse assembly? 3. What are the dynamics of adhesion, presynaptic active zone assembly and nascent presynaptic function following cell-cell contact at synaptic sites? This work will provide fundamental new information about presently unexplored mechanisms of CNS synapse formation. This information should illuminate the processes responsible for both normal and pathological development and growth of the nervous system, especially the creation of synaptic circuit topologies. Experiments addressing effects of electrical activity and neurotransmitters on synaptogenesis should help explain how early experience effects brain development and may also provide insights into possible roles of new synapse formation in learning and memory. This work should also help in efforts to devise rational strategies to promote central nervous system regeneration and recovery of function following trauma and stroke.
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