This laboratory studies the molecules that regulate synapse development and plasticity, with particular emphasis on the role of neurotrophic factors. Traditionally, neurotrophic factors are defined as secretory proteins that regulate neuronal survival and differentiation. Recent studies have established a new concept that neurotrophic factors also play important roles in synapse transmission and plasticity in both developing and adult nervous system. Two types of regulation have been discovered: acute modulation of synaptic transmission and plasticity, and long-term alteration of the structure and function of synapses. These studies have brought together two hotly pursued areas, function of neurotrophins and mechanisms of synaptic plasticity, and created an exciting new field of research. Continuous studies in this emerging field will help understand how synapses develop and function in the brain, and may have general implications in treating neurological disorders in both children and adults. This laboratory was among the first to study the synaptic functions of neurotrophic factors. A combined molecular biological and electrophysiological techniques are employed to study the regulatory effects of neurotrophic factors on the synapses at the neuromuscular junction and in the central nervous system such as hippocampus. We have made two important discoveries. One is that brain-derived neurotrophic factor (BDNF) acutely facilitates hippocampal LTP, a cellular model for learning and memory. This is achieved, at least in part, by enhancing synaptic responses to high frequency, tetanic stimulation and facilitation of synaptic vesicle docking. The second is that BDNF and neurotrophin-3 (NT3) promotes the long-term maturation at developing neuromuscular junction (NMJ). Both structure and function of the NMJ are altered after prolonged exposure to the neurotrophins. We found that unlike the acute effects, the long-term regulation requires the internalization of neurotrophin-Trk receptor complex, new protein synthesis, and the transcription factor CREB. Our recent work focuses on the molecular mechanisms underlying the acute and long-term neurotrophic regulation, and their relationships. Ongoing projects include: 1) neurotrophic regulation of long-lasting hippocampal synaptic plasticity, using transgenic/knockout mice; 2) biochemical and molecular study of activity-dependent modulation of BDNF receptor trafficking in hippocampal neurons; 3) molecular study of the signaling mechanisms for acute and long-term neurotrophic regulation, using Xenopus nerve-muscle system.

Selected Publications: