Actin Out: Regulation of the Synaptic Cytoskeleton

Abstract

The small size of dendritic spines belies the elaborate role they play in excitatory synaptic transmission and ultimately complex behaviors. The cytoskeletal architecture of the spine is predominately composed of actin filaments. These filaments, which at first glance might appear simple, are also surprisingly complex. They dynamically assemble into different structures and serve as a platform for orchestrating the elaborate responses of the spine during spinogenesis and experience-dependent plasticity. Multiple mutations associated with human neurodevelopmental and psychiatric disorders involve genes that encode regulators of the synaptic cytoskeleton. A major, unresolved question is how the disruption of specific actin filament structures leads to the onset and progression of complex synaptic and behavioral phenotypes. This review will cover established and emerging mechanisms of actin cytoskeletal remodeling and how this influences specific aspects of spine biology that are implicated in disease.

Keywords: Arp2/3 complex; Rho (Rho GTPase); WASH; actin; adhesion; cofilin; dendritic spine; formin; synapse; synaptic plasticity.

FIGURE 1.

Organization of distinct actin pools in dendritic spines. Shown is a schematic depicting the spatial organization of actin dynamics within different regions of the spine. Two types of actin, Arp2/3-dependent (red) and formin-based actin (orange), are delineated. Regions of the spine referenced in the text, including the synaptic zone, spine neck, and filopodial-like projections, are also labeled.

FIGURE 2.

The basics of actin dynamics in the dendritic spine. A, representative image of a dendritic section from a hippocampal neuron expressing GFP-actin. Fluorescent signal is pseudo-colored for relative intensity ranging from low (blue) to high (red). Note that actin is highly enriched in spines protruding from the dendritic shaft. B, schematic depicting actin turnover in dendritic spines and the proteins directly involved in its remodeling. Treadmilling of actin between polymerized F-actin to monomeric G-actin at the barbed (+) versus pointed (−) end is indicated.

FIGURE 3.

Actin signaling pathways and their association with brain disorders. Shown is a schematic of proteins involved in regulating the spine actin cytoskeleton. The synaptic actin cytoskeleton is a common pathway in which mutations are associated with increased risk for brain disorders. Each protein highlighted by yellow stars has a genetic mutation associated with ID, SZ, or ASD, each of which are indicated in parentheses. Finally, the dashed lines surrounding the Arp2/3 complex and cofilin indicate the final points of signaling output for actin remodeling, both of which have been studied extensively through knock-out mouse studies. Loss of Arp2/3 complex activity in the mouse forebrain mimics aspects of psychiatric conditions such as schizophrenia-related disorders, whereas loss of cofilin is associated with decreased anxiety in mice. ROCK, Rho-associated kinase.