Activity-Dependent Regulation of Early Stages in Synapse Formation

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Laura N. Borodinsky Proposal # 0516871Activity-dependent regulation of early stages in synapse formationNervous system function relies on the establishment of appropriate connections, called synapses. The hypothesis of the proposed project is that early events in synapse formation are shaped by electrical activity. Alterations in electrical activity modify neurotransmitter expression following a homeostatic paradigm (Borodinsky et al., 2004). This finding leads to the question whether altered neurotransmitter expression causes rerouting of axons in the spinal cord. Axonal pathfinding patterns for different neuronal types will be followed after activity has been perturbed. The experiments will also address the hypothesis that neural activity influences the classes of neurotransmitter receptors expressed in postsynaptic cells. The ultimate goal of the project will be to test the hypothesis that novel synapses between neurons and target cells can be formed when activity is manipulated, i.e. that expression of different transmitters will be matched by the expression of corresponding receptors. The proposed project is important for the field of developmental neuroscience because it challenges the view that early events in nervous system development are governed entirely by a predetermined genetic program, independent of electrical activity.The information gained in this study could have significant implications for how we think about disorders in developmental wiring of the nervous system and related pathologies. The ability to regulate the number of neurons secreting particular transmitters and transmitter sensitivity in target cells has the power to be of substantial societal benefit, providing potential therapies for neurological disorders.Support from NSF for the present proposal will be crucial in the advancement as an independent scientist of a member of an underrepresented group. This grant will allow continued training of students, and will allow the principal investigator to develop skills as a supervisor. NSF support will ensure publication of results in scientific journals, and participation in scientific meetings to disseminate the results from this proposal and enhance understanding of nervous system development.