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Title page for ETD etd-03272008-132508


Type of Document Dissertation
Author Wegner, Adam Michael
Author's Email Address adam.wegner@vanderbilt.edu
URN etd-03272008-132508
Title WASP family members and the Arp2/3 complex are critical regulators of actin in the development of dendritic spines and synapses in hippocampal neurons
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Terry L. Page Committee Chair
Alissa M. Weaver Committee Member
Donna J. Webb Committee Member
Gregory C. Mathews Committee Member
Keywords
  • Microfilament proteins
  • actin
  • N-WASP
  • synapse formation
  • spine morphogenesis
  • Arp2/3 complex
  • Dendrites
  • Neuroplasticity
Date of Defense 2008-03-20
Availability unrestricted
Abstract
Changes in the number, size, and shape of dendritic spines are associated with synaptic plasticity, which underlies cognitive functions such as learning and memory. This plasticity is attributed to reorganization of actin, but the molecular signals that regulate this process are poorly understood. In this study, we show that neural Wiskott-Aldrich syndrome protein (N-WASP) regulates the formation of dendritic spines and synapses in hippocampal neurons. N-WASP localized to spines and active, functional synapses as shown by loading with FM4-64 dye. Knockdown of endogenous N-WASP expression by RNAi or inhibition of its activity by treatment with a specific inhibitor, wiskostatin, caused a significant decrease in the number of spines and excitatory synapses. Deletion of the C-terminal VCA region of N-WASP, which binds and activates the Arp2/3 complex, dramatically decreased the number of spines and synapses, suggesting that activation of the Arp2/3 complex is critical for spine and synapse formation. Consistent with this, Arp3, like N-WASP, was enriched in spines and excitatory synapses and knockdown of Arp3 expression impaired spine and synapse formation. A similar defect in spine and synapse formation was observed when expression of an N-WASP activator, Cdc42, was knocked down. Thus, activation of N-WASP and subsequently the Arp2/3 complex appears to be an important molecular signal for regulating spines and synapses. Arp2/3 mediated branching of actin could be a mechanism by which dendritic spine heads enlarge and subsequently mature. Collectively, our results point to a critical role for N-WASP and the Arp2/3 complex in spine and synapse formation.
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