Abstract
AMPA receptor (AMPAR) trafficking is a key determinant of synaptic strength and synaptic plasticity. Under basal conditions, constitutive trafficking maintains surface AMPARs by internalization into the endosomal system, where the majority are sorted and targeted for recycling back to the plasma membrane. NMDA receptor (NMDAR)-dependent Long-Term Depression (LTD) is characterised by a reduction in synaptic strength, and involves endosomal sorting of AMPARs away from recycling pathways to lysosomes. The mechanisms that determine whether AMPARs are trafficked to lysosomes or to recycling endosomes, especially in response to NMDAR stimulation, are unclear. Here, we define a role for the actin-regulatory protein cortactin as a mediator of AMPAR endosomal sorting by direct interaction with the GluA2 subunit. Disrupting GluA2-cortactin binding in neurons causes the targeting of GluA2/A3-containing receptors to lysosomes and their consequent degradation, resulting in a loss of surface and synaptic GluA2 under basal conditions and an occlusion of subsequent LTD expression. Furthermore, we show that NMDAR stimulation causes a dissociation of endogenous cortactin from GluA2 via tyrosine phosphorylation of cortactin. These results demonstrate that cortactin maintains GluA2/A3 levels by directing receptors away from lysosomes, and that disrupting GluA2-cortactin interactions to target GluA2/A3 to lysosomes is an essential component of LTD expression.
Highlights
Long-term synaptic plasticity is thought to underlie learning and memory and the fine-tuning of neural circuitry during development
We explored the region of GluA2 C-terminus that binds cortactin by performing pulldowns with GST-GluA2 containing pairwise alanine substitutions, and found that a region close to the transmembrane domain was critical for cortactin binding
We define a new role for cortactin as a regulator of AMPA receptors (AMPARs) endosomal sorting by direct interaction with GluA2 subunit
Summary
Long-term synaptic plasticity is thought to underlie learning and memory and the fine-tuning of neural circuitry during development. AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the brain, and plasticity at excitatory synapses requires alterations in AMPAR number at the synaptic plasma membrane brought about by regulated trafficking of AMPAR-containing vesicles. NMDA receptor (NMDAR)-dependent LTD requires an increase in clathrin-mediated endocytosis to internalize AMPARs from the plasma membrane, and endosomal sorting steps whereby internalized AMPARs are targeted for lysosomal degradation, instead of recycling to the plasma membrane[9,10,11,12]. In non-neuronal cells, cortactin is recruited to endocytic sites, suggesting a role in regulating actin polymerization during clathrin-mediated endocytosis[17], and it is localized to subdomains of sorting endosomes, suggesting it plays a role in recycling of specific cargo[18]. Mutant cortactin that does not bind GluA2 causes lysosomal targeting and degradation of GluA2/A3-containing AMPARs, and a consequent reduction in surface and synaptic GluA2, which occludes subsequent induction of hippocampal LTD
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