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.

Fig. 1

(A) A GFP-expressing hippocampal neuron at day 14 in vitro displays dendritic filopodia-like protrusions and spines with different shapes and sizes (B, C) The high magnification image of the dendrite (B) and a drawing show examples of main categories of dendritic protrusions: filopodia-like protrusions, mushroom spine, thin spine, and stubby spine. (C) Filopodia-like protrusions are precursors of dendritic spines. Mature mushroom spines display the largest heads and thin necks.

Fig. 2

Arp2/3 nucleates new branches from existing actin filaments, creating fast-growing barbed ends.

Fig. 3

Regulatory proteins affecting the activity of Arp2/3.

Fig. 4

Opposing actions of profilin on actin. G-actin-sequestering promotes F-actin depolymerization, while profilin-actin complex induces polymerization by binding to F-actin barbed ends and promoting formation of ATP-actin monomers.

Fig. 5

Spinophilin participates in localization of PP1 to the cell membrane, where it dephosphorylates NMDA and AMPA receptors, down-regulating their activity. The actin-bundling activity of spinophilin prevents outgrowth of filopodia-like protrusions.

Fig. 6

Actin-severing activity of cofilin promotes F-actin and spine remodeling.

Fig. 7

Regulatory proteins that enhance or inhibit the activity of cofilin.