Accelerators, Brakes, and Gears of Actin Dynamics in Dendritic Spines

Abstract

Dendritic spines are actin-rich structures that accommodate the postsynaptic sites of most excitatory synapses in the brain. Although dendritic spines form and mature as synaptic connections develop, they remain plastic even in the adult brain, where they can rapidly grow, change, or collapse in response to normal physiological changes in synaptic activity that underlie learning and memory. Pathological stimuli can adversely affect dendritic spine shape and number, and this is seen in neurodegenerative disorders and some forms of mental retardation and autism as well. Many of the molecular signals that control these changes in dendritic spines act through the regulation of filamentous actin (F-actin), some through direct interaction with actin, and others via downstream effectors. For example, cortactin, cofilin, and gelsolin are actin-binding proteins that directly regulate actin dynamics in dendritic spines. Activities of these proteins are precisely regulated by intracellular signaling events that control their phosphorylation state and localization. In this review, we discuss how actin-regulating proteins maintain the balance between F-actin assembly and disassembly that is needed to stabilize mature dendritic spines, and how changes in their activities may lead to rapid remodeling of dendritic spines.

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“…It is thus conceivable that cofilin and cortactin may produce two coordinated effects on the actin network for AMPAR insertion: cofilin‐severing activity increases the number of preferred ends for Arp2/3 nucleation (Ichetovkin et al. , 2002), and cortactin can bind to and activate the Arp2/3 complex favoring the stabilization of the actin network (Pontrello & Ethell, 2009). As shown by Allison et al.…”

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

“…Activated LimK1, in turn, phosphorylates and inactivates its target cofilin. Cofilin is a depolymerizing factor and major determinant of dendritic spine structure; cofilin severs the actin filament (F-actin) at its pointed ends (Bamburg and Bernstein, 2010;Mizuno, 2013) and thereby regulates spine morphology, spine motility, and synaptic plasticity (Bosch and Hayashi, 2012;Hotulainen and Hoogenraad, 2010;Lin and Webb, 2009;Pontrello and Ethell, 2009). Growing evidence from studies involving non-neuronal cells indicates that mTORC2 regulates the actin cytoskeleton through Rac1 (Herná ndez-Negrete et al, 2007;Huang et al, 2013).…”

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“…Once activated, ROCK phosphorylates LIMK, which phosphorylates cofilin and inhibits its ability to sever actin filaments (Arber et al, ; Yang et al, ; Bamburg and Wiggan, ). Actin severing contributes to actin filament turnover, but it can also stimulate actin polymerization because it provides a new free actin filament plus end that can elongate, and both processes are likely critical for dendritic spine remodeling (Okamoto et al, ; Pontrello and Ethell, ; Shi et al, ). Actin polymerization and filament turnover are believed to occur in distinct subcellular compartments within the dendritic spine and are modulated by various cytoskeletal regulatory proteins localized to these regions (Oser and Condeelis, ; van Rheenen et al, ).…”