Abstract
SNX6 is a ubiquitously expressed PX-BAR protein that plays important roles in retromer-mediated retrograde vesicular transport from endosomes. Here we report that CNS-specific Snx6 knockout mice exhibit deficits in spatial learning and memory, accompanied with loss of spines from distal dendrites of hippocampal CA1 pyramidal cells. SNX6 interacts with Homer1b/c, a postsynaptic scaffold protein crucial for the synaptic distribution of other postsynaptic density (PSD) proteins and structural integrity of dendritic spines. We show that SNX6 functions independently of retromer to regulate distribution of Homer1b/c in the dendritic shaft. We also find that Homer1b/c translocates from shaft to spines by protein diffusion, which does not require SNX6. Ablation of SNX6 causes reduced distribution of Homer1b/c in distal dendrites, decrease in surface levels of AMPAR and impaired AMPAR-mediated synaptic transmission. These findings reveal a physiological role of SNX6 in CNS excitatory neurons.
Highlights
SNX6 is a member of the sorting nexin (SNX) family that plays important roles in retromer-mediated, dyneinÀdynactin-driven retrograde vesicular transport from endosomes to the trans-Golgi network (TGN)
By simultaneous recording the evoked EPSCs on infected and adjacent uninfected CA1 pyramidal neurons, we found that amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR)-mediated eEPSCs were significantly impaired by about 50% with ablation of SNX6 (Figure 9B), whereas N-methyl-D-aspartate receptor (NMDAR)-mediated eEPSCs and the pair-pulse ratio of AMPAR eEPSCs were
We demonstrate that ablation of SNX6 in the central nervous system (CNS) causes deficits in spatial learning and memory, a hippocampal-dependent brain function
Summary
SNX6 is a member of the sorting nexin (SNX) family that plays important roles in retromer-mediated, dyneinÀdynactin-driven retrograde vesicular transport from endosomes to the trans-Golgi network (TGN). SNX6 contains an amino-terminal Phox Homology (PX) domain that is evolutionarily conserved among SNXs and a carboxyl-terminal Bin/Amphiphysin/Rvs (BAR) domain that allows for dimerization with BAR domains of other proteins. It dimerizes with the SNX1 subunit of retromer through its BAR domain and binds to dynactin p150Glued through its PX domain, linking the dyneinÀdynactin motor complex to retromer-associated vesicular cargoes (Hong et al, 2009; Wassmer et al, 2009).
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