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Cytoskeleton Regulation of Dendritic Spines

by
Jaiping Gu
Bachelor of Science, 2004
Tsinghua University
Beijing, China

Thesis Advisor: James Q. Zheng
Graduate Program: Neuroscience

Research Tower
Room V-10

Thursday, July 30, 2009
2:30 pm


Abstract

Dendritic spines, small membranous protrusions from dendritic shafts, serve as postsynaptic terminals for most excitatory synapses. Spines are highly plastic, undergoing short and long-term modulation during development, as well as learning and memory. Two key events underlying long-term modulation of spines are: (1) neurotransmitter receptor trafficking to or from postsynaptic membrane; (2) change of spine size. Understanding the corresponding cellular and molecular mechanisms is critical to understand how brain works. Cytoskeleton controls many aspects of cell motility and intracellular trafficking, and also participates in spine plasticity. However, the role of cytoskeletal regulation in the postsynaptic plasticity remains poorly understood. Therefore, the focus of my thesis project is to understand how cytoskeleton controls and regulates dendritic spine development and plasticity.

While actin filaments are widely thought to be the sole cytoskeletal component in spines, I have consistently detected a small population of spines containing microtubules by confocal live-cell imaging. Importantly, using shRNA to knockdown a neuronal microtubule plus-end tracking protein (+TIP), EB3, I observed significantly reduced spine density. In addition, stabilization and disruption of microtubules by taxol and nocodazole enhanced and impaired spine plasticity evoked by brain-derived neurotrophic factor (BDNF), respectively. These results suggest that microtubules play an important role in spine development and dynamics.

In the second part of my thesis work, I examined a novel role of actin cytoskeleton in postsynaptic receptor trafficking, besides its predominant role in regulation of spine structure. Taking advantage of the pH-dependent fluorescence emission of super-ecliptic pHluorin (SEP)-GluR1 fusion proteins, I found that chemical LTP (cLTP) induced by tetraethylammonium (TEA) caused rapid and marked insertion of SEP-GluR1 onto the postsynaptic surfaces, without significant alteration of spine density or morphology. Disruption of actin dynamics by low concentrations of drugs inhibited TEA-induced GluR1 insertion, but did not alter the baseline SEP-GluR1 level. Furthermore, elevation of ADF/cofilin activity by either peptide inhibition of upstream LIM kinases or overexpression of constitutively active ADF/cofilin significantly enhanced GluR1 insertion after cLTP, whereas inhibition of ADF/cofilin activity abolished GluR1 insertion. Taken together, these findings show a novel function for ADF/cofilin-mediated actin dynamics in receptor trafficking.


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