SPIN90 dephosphorylation is required for cofilin-mediated actin depolymerization in NMDA-stimulated hippocampal neurons

Abstract

Actin plays a fundamental role in the regulation of spine morphology (both shrinkage and enlargement) upon synaptic activation. In particular, actin depolymerization is crucial for the spine shrinkage in NMDAR-mediated synaptic depression. Here, we define the role of SPIN90 phosphorylation/dephosphorylation in regulating actin depolymerization via modulation of cofilin activity. When neurons were treated with NMDA, SPIN90 was dephosphorylated by STEP61 (striatal-enriched protein tyrosine phosphatase) and translocated from the spines to the dendritic shafts. In addition, phosphorylated SPIN90 bound cofilin and then inhibited cofilin activity, suggesting that SPIN90 dephosphorylation is a prerequisite step for releasing cofilin so that cofilin can adequately sever actin filaments into monomeric form. We found that SPIN90 YE, a phosphomimetic mutant, remained in the spines after NMDAR activation where it bound cofilin, thereby effectively preventing actin depolymerization. This led to inhibition of the activity-dependent redistribution of cortactin and drebrin A, as well as of the morphological changes in the spines that underlie synaptic plasticity. These findings indicate that NMDA-induced SPIN90 dephosphorylation and translocation initiates cofilin-mediated actin dynamics and spine shrinkage within dendritic spines, thereby modulating synaptic activity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-013-1391-4) contains supplementary material, which is available to authorized users.

Effective expression of Drebrin in hippocampus improves cognitive function and alleviates lesions of Alzheimer's disease in APP (swe)/PS1 (ΔE9) mice

“…The majority of the studies on Drebrin were conducted on a molecular and cellular level to explore its structure and function. Furthermore, most in vivo studies concentrate on its effects with upstream proteins but lack research focused on Drebrin's impact on cognitive behavior in AD . In this study, to explore the regularity of age, meticulous behavioral tests were conducted in APP/PS1 mice aged 4‐16 months.…”

“…Furthermore, most in vivo studies concentrate on its effects with upstream proteins but lack research focused on Drebrin's impact on cognitive behavior in AD. 19,23,24 In this study, to explore the regularity of age, meticulous behavioral tests were conducted in APP/PS1 mice aged 4-16 months. A correlation analysis between Drebrin levels and behavioral data was performed.…”

Drebrin inhibits cofilin‐induced severing of F‐actin

“…Cofilin upregulation followed by the translocation of drebrin A from DS was proposed to be part of a pathological pathway relevant to Alzheimer's disease (AD), Down syndrome, and epilepsy [Kojima and Shirao, ; Ferhat, ]. This pathway, which was suggested to lead to spine shrinkage and the impairment of higher order brain function, can be a potential therapeutical target for complex brain disorders [Zhou et al, ; Cho et al, ]. However, the molecular details of drebrin‐cofilin cross‐talk are poorly understood.…”

SPIN90 Modulates Long-Term Depression and Behavioral Flexibility in the Hippocampus

“…Cell line culture was performed as described previously (Cho et al, 2013b ). HeLa cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM; Gibco, Waltham, MA, USA, 12100-046) supplemented with 10% fetal bovine serum.…”

“…HeLa cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM; Gibco, Waltham, MA, USA, 12100-046) supplemented with 10% fetal bovine serum. Primary neuronal cultures were performed as described previously (Cho et al, 2013b ). Briefly, hippocampi from wildtype (WT) and Spin90 -KO embryonic mice (E18–19) were extracted and cultured in neurobasal medium (Invitrogen, Waltham, MA, USA) supplemented with B27 (Gibco, 10889038) and 2 mM GlutaMAX (Gibco, 35050061).…”