Synapses represent the basic unit of neuronal communications and are composed of paired pre- and post-synaptic terminals. Most of the excitatory synapses reside on dendritic spines, a type of dendritic protrusion that hosts neurotransmitter receptors and other postsynaptic specializations. Synapses are plastic and undergo short- and long-term modifications during developmental refinement of neuronal circuitry, as well as during learning and memory. Synaptic modifications involve both pre- and post-synaptic changes. At the postsynaptic site, directed trafficking of neurotransmitter receptors to and from the membrane surface is believed to be a key event underlying long-term potentiation (LTP) and depression (LTD), respectively. In addition, dendritic spines undergo rapid changes in their morphology in association with the plasticity. The underlying cellular mechanisms that control and regulate these rapid changes in postsynaptic receptors and spine structures remain to be fully elucidated. In this proposed project, we plan to investigate the cytoskeletal mechanisms that regulate postsynaptic dynamics and plasticity. We hypothesize that the actin eytoskeleton controls spine dynamics and receptor trafficking at the postsynaptic site and MTs contribute to spine development. We will take advantage of our imaging expertise and experience in studying cytoskeletal dynamics in cultured neurons and organotypic slices to understand the cytoskeletal regulation of postsynaptic structures and functions.
Three specific aims are proposed: (1) Cytoskeletal regulation of spine plasticity (2) ADF/cofilin in spine dynamics and receptor trafficking during plasticity (3) Local synthesis and degradation of actin-associated proteins during plasticity.
Since many neural disorders are associated with alterations in synaptic connections, our study will not only provide a better understanding of the molecular and cellular mechanisms underlying synaptic plasticity, but also shed light on brain development and functions under both physiological and pathological conditions.
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