All ETDs from UAB

Advisory Committee Chair

Gavin Rumbaugh

Advisory Committee Members

Lori L McMahon

J David Sweatt

Jacques I Wadiche

Scott Wilson

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

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.

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