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.Dendritic spines are morphologically diverse, actin-rich protrusions emerging from dendritic shafts that serve as the receiving sites for the majority of excitatory synaptic transmission in the brain. First described over a century ago by Ramón y Cajal, dendritic spines typically consist of a spine head, which can range in size from 0.5 to 2 m in length, and thin spine neck (ϳ0.2 m thick) (Fig. 1). Their essential function is to compartmentalize biochemical and electrical signals in response to synaptic activation (1). Dendritic spines are supported by an underlying cytoskeleton that is almost exclusively composed of actin filaments, which can be up to ϳ200 nm long (2). Remodeling of this densely packed actin governs most, if not all, dendritic spine physiology. This includes spine formation and maintenance, synaptic adhesion, receptor endocytosis and exocytosis, and synaptic plasticity (Fig. 1). Further, the actin cytoskeleton drives dendritic spine turnover and morphological changes that occur in vivo in response to experience (3). Finally, aberrations in dendritic spine morphology and density are linked to a variety of neurological disorders such as schizophrenia (SZ) 2 and intellectual disability (ID) (4). Recent studies link de novo mutations associated with increased risk of complex psychiatric disorders such as SZ to genes encoding regulators of the post-synaptic actin cytoskeleton (5) (see Fig. 3). Together these findings strongly imply that proper maintenance of the spine actin cytoskeleton is critical for spine functionality and neuronal connectivity. This review will focus on the nuts and bolts of actin dynamics in spines as well as recent developments in the modulation of the synaptic cytoskeleton in two crucial dendritic spine processes whose disturbances are linked with synapse pathologies: synaptic adhesion and synaptic plasticity.

Assessment of brain reference genes for RT-qPCR studies in neurodegenerative diseases

“…Our data indicate that GAPDH is not a stable RG in neither the PFC (ranked 12 th ) nor the CB (ranked 6 th ). ACTB protein is one of six different human actin isoforms and is one of the two non-muscle cytoskeletal actins48. ACTB has also been used extensively as an RG for several years.…”

Regulation of Blood-Testis Barrier (BTB) Dynamics, Role of Actin-, and Microtubule-Based Cytoskeletons

“…F-actin is a polymer and an intrinsic polarized structure formed by G-actin subunits assembled from the fast-growing end (also called the barbed end or plus (+) end) through the action of nucleation proteins vs . the slow-growing end known as the pointed end or minus (−) end [10, 52, 53]. In order for actin to undergo continuous remodeling, actin microfilaments undergo rapid changes including polymerization (or nucleation), depolymerization, bundling, severing (or cleavage), capping, and branching via the action of different actin-binding and regulatory proteins.…”

Proteomic analysis of mucopolysaccharidosis I mouse brain with two-dimensional polyacrylamide gel electrophoresis

“…More importantly, SXTBP1 (syntaxin binding protein 1) is a regulator of synaptic vesicle docking and fusion, which has also been found to interact with cytoskeletal proteins (25). Further, synaptic plasticity requires the dynamic actin filaments, which is the major structural component of synapses (reviewed in 26). These findings indicate the downregulation of cytoskeletal proteins may affect synaptic transmission directly or indirectly through SXTBP1.…”