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Review
. 2015 Sep;72(18):3521-9.
doi: 10.1007/s00018-015-1941-z. Epub 2015 Jun 3.

ADF/cofilin: a crucial regulator of synapse physiology and behavior

Marco B Rust  1
Affiliations
Review

ADF/cofilin: a crucial regulator of synapse physiology and behavior

Marco B Rust. Cell Mol Life Sci. 2015 Sep.

Abstract

Actin filaments (F-actin) are the major structural component of excitatory synapses, being present in presynaptic terminals and in postsynaptic dendritic spines. In the last decade, it has been appreciated that actin dynamics, the assembly and disassembly of F-actin, is crucial not only for the structure of excitatory synapses, but also for pre- and postsynaptic physiology. Hence, regulators of actin dynamics take a central role in mediating neurotransmitter release, synaptic plasticity, and ultimately behavior. Actin depolymerizing proteins of the ADF/cofilin family are essential regulators of actin dynamics, and a number of recent studies highlighted their crucial functions in excitatory synapses. In dendritic spines, ADF/cofilin activity is required for spine enlargement during initial long-term potentiation (LTP), but needs to be switched off during spine stabilization and LTP consolidation. Conversely, active ADF/cofilin is needed for spine pruning during long-term depression (LTD). Moreover, ADF/cofilin controls activity-induced synaptic availability of glutamate receptors, and exocytosis of synaptic vesicles. These data show that the activity of ADF/cofilin in synapses needs to be spatially and temporally tightly controlled through several upstream regulatory pathways, which have been identified recently. Hence, ADF/cofilin-controlled actin dynamics emerged as a critical and central regulator of synapse physiology. In this review, I will summarize and discuss our current knowledge on the roles of ADF/cofilin in synapse physiology and behavior, by focusing on excitatory synapses of the mammalian central nervous system.

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Figures

Fig. 1
Fig. 1
A schematic diagram summarizing the functions of cofilin1 in dendritic spines. Under basal conditions (b), before induction of either LTP or LTD, cofilin1 is present in dendritic spines [23]. Electron microscopy revealed an enrichment of cofiin1 in the spine head periphery [19], are sub-spinous region with a more dynamic actin network compared to the spine head core or the spine neck [27]. Under non-stimulated conditions, cofilin1 controls lateral diffusion of AMPAR, presumably via an actin-dependent mechanism [21]. Upon LTP induction (c), more cofilin1 moves into dendritic spines and this translocation is required for actin polymerization and spine enlargement [23]. Moreover, cofilin1-dependent actin dynamics control the synaptic accumulation of AMPAR during LTP [22]. Thereafter, during consolidation of structural changes (d), cofilin1 becomes phosphorylated (inactivated) and accumulates at the center to base sub-region of the spine head [22, 23]. a Upon induction of LTD, cofilin1 moves into dendritic spines [35], and cofilin1-dependent disassembly of F-actin mediates spine shrinkage [4]. Arrows indicate lateral diffusion of AMPAR in the extra-synaptic membrane
Fig. 2
Fig. 2
A schematic diagram showing the presynaptic defects in ADF/cofilin mutant mice. Compared to controls (a), the distribution of synaptic vesicles within the presynaptic bouton is changed in double mutants lacking cofilin1 and ADF (b) [24]. Moreover, the number of docked vesicles is increased. Electrophysiological experiments revealed an impairment in the recruitment of synaptic vesicles (indicated by a thinner arrow in the presynaptic terminal of double mutants when compared to controls) and an increase in synaptic vesicle exocytosis [24, 25]. No such defects were noted in cofilin1 or ADF single mutants [18, 21], thereby demonstrating that cofilin1 and ADF have redundant and overlapping functions in presynaptic physiology
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