Learning, AMPA receptor mobility and synaptic plasticity depend on n-cofilin-mediated actin dynamics

Abstract

Neuronal plasticity is an important process for learning, memory and complex behaviour. Rapid remodelling of the actin cytoskeleton in the postsynaptic compartment is thought to have an important function for synaptic plasticity. However, the actin-binding proteins involved and the molecular mechanisms that in vivo link actin dynamics to postsynaptic physiology are not well understood. Here, we show that the actin filament depolymerizing protein n-cofilin is controlling dendritic spine morphology and postsynaptic parameters such as late long-term potentiation and long-term depression. Loss of n-cofilin-mediated synaptic actin dynamics in the forebrain specifically leads to impairment of all types of associative learning, whereas exploratory learning is not affected. We provide evidence for a novel function of n-cofilin function in synaptic plasticity and in the control of extrasynaptic excitatory AMPA receptors diffusion. These results suggest a critical function of actin dynamics in associative learning and postsynaptic receptor availability.

Attention-Deficit/Hyperactivity Disorder–like Phenotype in a Mouse Model with Impaired Actin Dynamics

“…We noted altered behavior in ACC mice, which lack ADF systemically and n-cofilin specifically in the adult telencephalon (16,20). The mice appeared more active compared with controls or single mutants, for example, on opening of the cage and removal of nest material (Supplemental Video S1 in Supplement 2).…”

“…Two family members, ADF and n-cofilin, are highly abundant in the adult brain and present in excitatory synapses (16)(17)(18). Analyses of gene-targeted mice revealed the relevance of n-cofilin for postsynaptic plasticity, learning, and anxiety (19,20). However, these analyses also suggested an overlapping function for ADF and n-cofilin.…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…Other potential mechanisms by which ApoE receptors may promote neuronal survival (Beffert et al 2006b) during aging involve signaling pathways that control microtubule and actin dynamics Assadi et al 2003;Brich et al 2003;Ohkubo et al 2003;Chai et al 2009;Forster et al 2010;Rust et al 2010), dendritogenesis (Niu et al 2004), spine formation (Niu et al 2008), glutamate receptor function and synaptic plasticity (Zhuo et al 2000;Weeber et al 2002;Beffert et al 2005;Chen et al 2005;D'Arcangelo 2005;Sinagra et al 2005;Groc et al 2007;Durakoglugil et al 2009;Korwek et al 2009;Chen et al 2010), as well as learning and memory (reviewed in Herz and Beffert 2000;Herz and Chen 2006;Bu 2009;Herz 2009). In this section we will mainly focus on the role of the ApoE receptors Apoer2 and Vldlr and their ligand Reelin in these processes.…”

“…The latter may, however, not be entirely dependent on Apoer2 and Vldlr (Chameau et al 2009) and may also involve interactions with APP (Hoe et al 2009). Reelin signaling also regulates dendritic spine morphology (Costa et al 2001;Niu et al 2008;Pujadas et al 2010), which likely involves regulation of actin dynamics and the participation of n-cofilin (Chai et al 2009;Rust et al 2010). It activates LIM kinase (LIMK), which inhibits the actin-depolymerizing activity of n-cofilin.…”

“…The dynamic remodeling of synaptic connections requires constant reorganization of actin filaments (Dillon and Goda 2005). Consequently, postnatal disruption of n-cofilin in mice leads to increased synapse density and enlargement of axospinous synapses (Rust et al 2010) with defects in long-term potentiation (LTP) and long-term depression (LTD). Although synaptic AMPA receptor mobility is not affected, diffusion of extrasynaptic AMPA receptors is reduced owing to F-actin stabilization, preventing efficient egress of AMPA receptors from the synaptic into the extrasynaptic domain, and thus LTD, in the n-cofilin mutants.…”