Endophilin A1 regulates dendritic spine morphogenesis and stability through interaction with p140Cap

Abstract

Dendritic spines are actin-rich membrane protrusions that are the major sites of excitatory synaptic input in the mammalian brain, and their morphological plasticity provides structural basis for learning and memory. Here we report that endophilin A1, with a well-established role in clathrin-mediated synaptic vesicle endocytosis at the presynaptic terminal, also localizes to dendritic spines and is required for spine morphogenesis, synapse formation and synaptic function. We identify p140Cap, a regulator of cytoskeleton reorganization, as a downstream effector of endophilin A1 and demonstrate that disruption of their interaction impairs spine formation and maturation. Moreover, we demonstrate that knockdown of endophilin A1 or p140Cap impairs spine stabilization and synaptic function. We further show that endophilin A1 regulates the distribution of p140Cap and its downstream effector, the F-actin-binding protein cortactin as well as F-actin enrichment in dendritic spines. Together, these results reveal a novel function of postsynaptic endophilin A1 in spine morphogenesis, stabilization and synaptic function through the regulation of p140Cap.

Endophilin‐A regulates presynaptic Ca 2+ influx and synaptic vesicle recycling in auditory hair cells

“…The reduced number of RA‐SVs at endophilin‐deficient AZs might indicate that endophilins are required for efficient resupply of SVs to the ribbon. Given that endophilins are capable of interacting with actin and/or actin‐modifying proteins such as intersectin (Ferguson et al , ; Soda et al , ; Vehlow et al , ; Pechstein et al , ; Yang et al , ), as well as that the F‐actin cytoskeleton is important for SV exocytosis in IHCs (Vincent et al , ; Guillet et al , ), an additional role of endophilin in SV resupply to the ribbon appears likely. Alternatively or in addition, endophilin binding to otoferlin at the release site might facilitate the lateral diffusion of fused vesicular proteolipids (site clearance) as proposed for AP‐2 (Jung et al , ).…”

Endophilin A1 Promotes Actin Polymerization in Dendritic Spines Required for Synaptic Potentiation

“…Endophilin A1 (or endophilin 1, EEN1) is a member of the evolutionarily conserved endophilin A family that is expressed almost exclusively in brain ( de Heuvel et al, 1997 ; Ringstad et al, 1997 , 2001 ), featuring an amino-terminal amphipathic helix-Bin/amphiphysin/Rvs (N-BAR) domain with membrane bending and curvature sensing capacities ( Farsad et al, 2001 ; Gallop et al, 2006 ; Frost et al, 2009 ; Bai et al, 2010 ), and a carboxyl-terminal Src Homology 3 (SH3) domain that binds to a number of protein partners ( Figure 1A ; Gad et al, 2000 ; Vinatier et al, 2006 ; Nakano-Kobayashi et al, 2009 ; Fu et al, 2011 ; Pechstein et al, 2015 ; Yang et al, 2015 ). Previous studies have established roles for endophilin As in recycling of synaptic vesicles through its interaction with the endocytic proteins synaptojanin, dynamin, and intersectin ( Verstreken et al, 2002 , 2003 ; Schuske et al, 2003 ; Milosevic et al, 2011 ; Pechstein et al, 2015 ), and regulation of neurotransmitter exocytosis through its binding to the glutamate transporter VGLUT1 ( Weston et al, 2011 ).…”

“…In hippocampal neurons, all three members of endophilin A family localize to both pre- and post-synaptic sites ( Chowdhury et al, 2006 ; Yang et al, 2015 ). Although knockout (KO) of individual endophilin A genes in mice does not affect life span and fertility, double knockout (DKO) of endophilin A1 and A2 (or endophilin 2, EEN2) genes causes progressive ataxia and neurodegeneration, and triple knockout (TKO) causes perinatal lethality ( Milosevic et al, 2011 ; Murdoch et al, 2016 ), suggesting functional redundancy among them in neurons.…”

“…At the postsynaptic site, endophilin A2 and A3 (or endophilin 3, EEN3) interact with the immediate early protein Arc/Arg3.1 to enhance endocytic trafficking of the AMPARs that likely contributes to synaptic plasticity and memory consolidation ( Chowdhury et al, 2006 ; Rial Verde et al, 2006 ). In dendritic spines, membrane protrusions from dendrites that are major postsynaptic sites for excitatory inputs, endophilin A1 interacts with the cytoskeleton regulator p140Cap and regulates spine morphogenesis and synapse formation during early neurodevelopment ( Yang et al, 2015 ). Whether or not postsynaptic endophilin A1 also functions in synaptic plasticity is unclear.…”

Proteomic Analysis of Mouse Brain Subjected to Spaceflight

“…Similarly, both dynamin 3 (DNM3) [38] and SH3 domain containing GRB2 like 2, endophilin A1 (SH3GL2) [39] that were upregulated in grey matter are involved with dendritic spine morphogenesis and stability. Another upregulated protein in the grey matter is actinin alpha 1 (ACTN1).…”