Actin Regulation of Dendritic Spine Development and Plasticity

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Project Summary Chemical synapses 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 during plasticity. The underlying cellular mechanisms that control and regulate these rapid changes in postsynaptic receptors and spine structures remain to be fully elucidated. The cytoskeleton controls many, if not all, aspects of the motility of cellular structures. How the cytoskeleton regulates postsynaptic structure, function, and modifications during plasticity, however, remains poorly understood. This proposed study aims to investigate novel actin mechanisms involving local G-actin regulation and structure-function coupling that enable the development of postsynaptic structure and specialization required for a functional synapse. Specifically, we will investigate the molecular mechanism underlying the spine enrichment of G-actin and its dynamic regulation during spine development. Furthermore, the study will a novel interaction between (+) end capping protein CP and Shank scaffolding protein in coupling the actin- based structural changes and the development of the postsynaptic specialization. Given that many neural disorders are associated with alterations in synaptic connections and plasticity, we hope to gain a better understanding of the molecular and cellular mechanisms underlying synaptic plasticity, which is of importance to our understanding of brain development and functions under both physiological and pathological conditions.