Neurotrophins (NTs), a family of proteins essential for the survival and differentiation of developing neurons, have been shown to participate in activity-dependent synaptic plasticity. In this project, we propose to test the hypothesis that secretion of NTs at developing synapses is triggered by synaptic activity in a spike pattern-dependent manner and localized synaptic actions of secreted NTs in turn produce long-term functional and structural modification of developing synaptic connections. We will focus our attention on brain-derived neurotrophic factor (BDNF), a NT widely expressed in the developing nervous system, using a combination of physiological, molecular biological, and optical imaging methods. The proposed research consists of three parts. In PART I, we will use cultures of rat or mouse hippocampal neurons to examine the acute pre- and postsynaptic effects of exogenously-applied BDNF on the function and plasticity of glutamatergic and GABAergic synapses and on axon/dendrite morphology and synaptogenesis. The synapse-specific local actions of BDNF and underlying signaling mechanisms will also be investigated. In PART II, we will study the role of endogenously-secreted BDNF in activity-induced modifications of synaptic function and morphology in hippocampal cultures, activity-dependent BDNF secretion, and intra- and interneuronal trafficking of BDNF. In PART Ill, using developing Xenopus tadpoles, we will examine the in vivo effect of BDNF on the function and plasticity of retinotectal synapses, axon/dendrite dynamics and synaptogenesis in the tectum, and the trafficking and secretion of endogenous BDNF. Finally, we will investigate the role of BDNF in the development of retinotopic map and direction-selective receptive field of tectal neurons. Taken together, these in vitro and in vivo studies provide unique opportunities to address several fundamental cell biological issues concerning the modulatory function of neurotrophins in activity-dependent refinement of developing neural connections, and are likely to yield new information relevant to our basic understanding of physiology and pathology of the developing nervous system.
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