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Review
. 2010 Oct;20(5):578-87.
doi: 10.1016/j.conb.2010.06.009.

A network of networks: cytoskeletal control of compartmentalized function within dendritic spines

Nicholas A Frost  1 , Justin M Kerr, Hsiangmin E Lu, Thomas A Blanpied
Affiliations
Review

A network of networks: cytoskeletal control of compartmentalized function within dendritic spines

Nicholas A Frost et al. Curr Opin Neurobiol. 2010 Oct.

Abstract

Almost 30 years ago, actin was identified as the major cytoskeletal component of dendritic spines. Since then, its role in the remarkable dynamics of spine morphology have been detailed with live-cell views establishing that spine shape dynamics are an important requirement for synaptogenesis and synaptic plasticity. However, the actin cytoskeleton is critical to numerous and varied processes within the spine which contribute to the maintenance and plasticity of synaptic function. Here, we argue that the spatial and temporal distribution of actin-dependent processes within spines suggests that the spine cytoskeleton should not be considered a single entity, but an interacting network of nodes or hubs that are independently regulated and balanced to maintain synapse function. Disruptions of this balance within the spine are likely to lead to psychiatric and neurological dysfunction.

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Figures

Figure 1
Figure 1. Actin regulates the PSD scaffold, and acts at other distinct locations throughout spines
A. Individual PSDs undergo morphological changes accompanied by internal changes in scaffold protein density. Hippocampal neuron 4 weeks in culture, transfected with PSD-95-GFP, and imaged by confocal microscopy. Color scale shows the proportion of total PSD-95 molecules per 1,000 nm2 in the image. (Spatial scale bar: 1 μm). Panels A-C adapted from Blanpied et al. [17**], copyright 2008 National Academy of Sciences, U.S.A. B. Actin drives changes in shape and spatial fluctuations of PSD-95 molecular density of individual PSDs. Same PSD as in A, after application of latrunculin A to prompt depolymerization of actin filaments. C. Increasing neuronal activity increases the rate of actin-driven PSD morphological change, as measured with a shape change index based on the variance of PSD shape over time. This increase is blocked by glutamate receptor antagonists. D. Summary of several known sites of actin regulation throughout individual spines, illustrating that the spine cytoskeleton is a network of networks that coordinately control synapse function via numerous distributed mechanisms. Gray arrows indicate direction of actin flow; green arrows indicate potential for cargo transport along filaments oriented in either direction.
Figure 2
Figure 2. Mechanisms of spatially restricting actin regulation
A. Treadmilling of actin mediated by addition of monomers at filament barbed ends (red arrow) and depolymerization by cofilin (blue wedge) at or near filament pointed ends. Polymerized actin molecules and binding proteins flow along the active filament as monomers are added. Gray arrows indicate direction and rate of flow. B. The pointed end of many filaments probably lie deep in the spine interior, and depolymerizing molecules are free to diffuse in the cytoplasm. Thus, even localized activation of signalling pathways near the spine membrane is likely to result in a widespread alteration of filament structure. For example, regulation of cofilin activity (by phosphorylation - yellow circle). C. Conversely, sites of ongoing monomer incorporation near the spine membrane are likely to be important sites for localized regulation of filament structure, because rates of monomer incorporation may be controlled by anchored or membrane-associated factors. D. Sites of assembly require profilin (yellow boxes), which is enriched near the PSD. This represents one known example of a potentially larger strategy for spatial regulation. E. Spatial pattern of branch formation is determined by localization of the Arp2/3 complex (blue complex), which has binding partners Abp1 and cortactin that bind the PSD scaffold Shank. F. Localization of signaling molecules including Kalirin-7, a Rho-GEF which binds PSD-95, may be responsible for the spatial segregation of downstream actin regulatory pathways. G. A number of actin binding proteins such as CaMKII are localized at the PSD through specific binding to PSD scaffolds. their ability to bind to and be transported away from the membrane by a growing actin filament may be a mechanism for controlling the number and composition of signalling molecules at the PSD. In addition, these molecules compete with other actin binding proteins for sites on the growing filament. H. A number of molecules, including CaMKII and alpha actinin, are localized at the synapse, and through association of multiple actin binding domains, have the ability to bundle actin filaments. I. Actin binding proteins compete for binding sites on growing filaments. Thus, the preferential decoration of filaments near the synapse with molecules such as CaMKII or cortactin may represent a protective mechanism which allows growing filaments to penetrate more deeply into the spine interior before they are severed by cofilin.
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References

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