Dissertation/Thesis Abstract

Myosin-II regulates actin dynamics critical for structural plasticity and memory
by Gavin, Cristin F., Ph.D., The University of Alabama at Birmingham, 2012, 152; 3550346
Abstract (Summary)

Dynamic changes to the actin cytoskeleton are required for synaptic plasticity and long-term memory formation. However, the molecular mechanisms that mediate filamentous actin ( F-actin) dynamics during both activity-dependent synaptic potentiation and long-term memory encoding are poorly understood. Myosin II motor proteins are highly expressed in actin-rich growth structures in neurons, including dendritic spines. Recent work demonstrates that these molecular machines mobilize F-actin in response to synaptic stimulation and are required for memory encoding in CA1 hippocampus of rodents. The aims of this project were two-fold. First, we sought to establish if myosin II regulates actin filament polymerization necessary for structural plasticity at individual synapses. To test this, we targeted single hippocampal spines in acute slices from GFP M line mice. Using 2-photon laser scanning microscopy (LSM) combined with targeted glutamate uncaging, we were able to evaluate the effects of myosin II motor activity on activity-dependent single spine plasticity. We found that myosin II potently regulates an early cytoskeletal-dependent processes that is critical for inducing and later stabilizing changes in spine volume. These studies provide a critical mechanistic link between glutamate receptor activation and de novo F-actin polymerization known to regulate dendritic spine structural plasticity, a process believed to underlie aspects of memory and cognition. The hippocampus and lateral amygdala (LA) share many molecular mechanisms of synaptic potentiation and memory formation. Because myosin II-dependent actin regulation is critical for structural and functional plasticity at CA1 synapses, as well as for long-term fear memory formation (LTM), we hypothesized that myosin II regulates an actin-dependent mechanism required for amygdala-dependent fear memory formation. To test this, we trained rats using a cued-fear conditioning paradigm combined with targeted intra-cranial infusions of small molecule inhibitors at different time points. We found that myosin II motors are critical for an early actin-dependent process that selectively facilitates long-term fear memory consolidation. Furthermore, using viral-mediated in vivo knockdown, we identified the IIB isoform of myosin as the critical regulator of this process. Taken together, these data support the idea that myosin II-dependent actin regulation is a general mechanism that supports memory consolidation in the mammalian CNS.

Indexing (document details)
Advisor: Rumbaugh, Gavin
Commitee: McMahon, Lori, Sweatt, J. David, Wadiche, Jacques I., Wilson, Scott
School: The University of Alabama at Birmingham
Department: Neurobiology
School Location: United States -- Alabama
Source: DAI-B 74/06(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Neurosciences
Keywords: Actin, Long term memory, Myosin ii, Single spine glutamate uncaging, Structural plasticity
Publication Number: 3550346
ISBN: 9781267873989
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