Thesis Abstract and Dissertation Abstracts

Myosin VI and myosin Ie in postsynaptic function

Thesis Abstract by Emily Osterweil from Date Submitted: Feb 14, 2007, 20:23

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, Yale Unitversity, 2005

Disseration Keywords: myosin, postsynaptic, AMPA, endocytosis

This Thesis Abstract | Dissertation Abstract may be cited as follows:
Osterweil, E. K. Myosin VI and myosin Ie in postsynaptic function. Yale University (2005). UMI publishing: AAT 3168963; ProQuest ID 888865211; ISBN 0542049503.

Thesis Abstract or Dissertation Abstract (Summary):
At postsynaptic density (PSD), fast excitatory transmission occurs through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid type glutamate receptors (AMPARs) and N-methyl-D-aspartate type glutamate receptors (NMDARs). The endocytosis of these receptors is required for normal synaptic activity, and has been linked to synaptic plasticity. Recently, filamentous (F)-actin has been shown to be important for AMPAR and NMDAR function, however the molecular mechanisms are poorly understood. Myosins, molecular motors that use ATP hydrolysis to move on F-actin, are important for the most basic of cellular processes, and two different myosins, myosin VI (Myo6) and myosin Ie (Myo1e) have been implicated in receptor-mediated endocytosis in non-neuronal cells. Myo6 associates with the clathrin adaptor protein AP-2, and expression of a dominant-negative Myo6 in fibroblasts has been shown to disrupt transferrin receptor endocytosis (Buss et al., 2001). In yeast and amoeba, Myo1e participates in endocytosis through the manipulation of F-actin, however the function of mammalian Myo1e is unknown (Tuxworth and Titus, 2000). We find that both Myo6 and Myo1e are expressed throughout the brain, localized to synapses and enriched at the PSD, where they exist in complexes with the AMPAR and NMDAR, respectively. These interactions are specific, as Myo6 does not interact with the NMDAR, and Myole does not interact with the AMPAR. Further, we find that the Myo6-AMPAR complex contains AP-2, and Myo1e directly binds to the endocytic proteins dynamin-1, dynamin-2 and synaptojanin-1. Consistent with this, we find that both myosins function in receptor-mediated endocytosis, and are required for synaptic structure. Specifically, Myo6 deficient ( Snell's waltzer ; sv / sv ) hippocampal neurons display a significant deficit in the stimulation-induced internalization of AMPARs, and neuroblastoma cells expressing a dominant-negative Myo1e display dysfunctional transferrin receptor endocytosis. In hippocampal neurons, disruption of either Myo6 or Myo1e leads to synapse loss, and disruption of Myo6 also leads to dendritic spine loss. In addition, sv / sv hippocampus exhibits a decrease in synapse number, abnormally short dendritic spines, and profound astrogliosis. These results provide roles for Myo6 and Myo1e in postsynaptic function and structure, and, importantly, provide one explanation for why excitatory synaptic transmission requires F-actin.

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