Abstract
Endophilin A1 is a member of the N-BAR domain-containing endophilin A protein family that is involved in membrane dynamics and trafficking. At the presynaptic terminal, endophilin As participate in synaptic vesicle recycling and autophagosome formation. By gene knockout studies, here we report that postsynaptic endophilin A1 functions in synaptic plasticity. Ablation of endophilin A1 in the hippocampal CA1 region of mature mouse brain impairs long-term spatial and contextual fear memory. Its loss in CA1 neurons postsynaptic of the Schaffer collateral pathway causes impairment in their AMPA-type glutamate receptor-mediated synaptic transmission and long-term potentiation. In KO neurons, defects in the structural and functional plasticity of dendritic spines can be rescued by overexpression of endophilin A1 but not A2 or A3. Further, endophilin A1 promotes actin polymerization in dendritic spines during synaptic potentiation. These findings reveal a physiological role of endophilin A1 distinct from that of other endophilin As at the postsynaptic site.
Highlights
We further show that endophilin A1 promotes actin polymerization required for the morphological and functional changes in dendritic spines of cultured hippocampal neurons during chemically induced long-term potentiation (LTP)
We uncovered a postsynaptic role of endophilin A1 in synaptic plasticity distinct from that of endophilin A2 and A3
Endophilin A1 is required for the physical enlargement and upregulation of AMPA-type glutamate receptors (AMPARs) expression in the postsynaptic membrane of dendritic spines during synaptic potentiation, whereas previous studies have indicated that endophilin A2 and A3 cooperate with the immediate early protein Arc/Arg3.1 to downregulate surface AMPARs by accelerating their endocytosis (Chowdhury et al, 2006)
Summary
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 carboxylterminal 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). Endophilin A1 Functions in Spine Potentiation 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 mammalian cells, they mark and control a clathrin-independent fast endocytic pathway of transmembrane receptors (Boucrot et al, 2015; Renard et al, 2015). Cell biological studies and electron microscopy analysis of DKO and TKO synapses reveal a role of endophilin As in clathrin uncoating after scission of endocytosed synaptic vesicles at the presynaptic site, a decrease in the amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSC) was detected in TKO neurons (Milosevic et al, 2011), implying changes in the number of the AMPA-type glutamate receptors (AMPARs) in postsynaptic plasma membrane that cannot be explained by their known functions
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