Parasynaptic NMDA receptor signaling couples neuronal glutamate transporter function to AMPA receptor synaptic distribution and stability

Abstract

At synapses, two major processes occur concomitantly after the release of glutamate: activation ofAMPAreceptors (AMPARs) to conduct synaptic transmission and activation of excitatory amino acid transporters (EAATs) for transmitter removal. Although crosstalk between the receptors and EAATs is conceivable, whether and how the transporter activity affectsAMPARsynaptic localization remain unknown. Using cultured hippocampal and cortical rat neurons, we show that inhibition of glutamate transporters leads to rapid reduction in AMPARsynaptic accumulation and totalAMPARabundance.EAATinactivity also results in elevated internalization and reduced surface expression of AMPARs. The reduction in AMPAR amount is accompanied by receptor ubiquitination and can be blocked by suppression of proteasome activity, indicating the involvement of proteasome-mediated receptor degradation. Consistent with glutamate spillover, effect of EAAT inhibition on AMPAR distribution and stability is dependent on the activation of parasynaptically localized NR2Bcontaining NMDA receptors (NMDARs). Moreover, we show that neuronal glutamate transporters, especially those localized at the postsynaptic sites, are responsible for the observed effect during EAAT suppression. These results indicate a role for neuron-specific glutamate transporters in AMPAR synaptic localization and stability. © 2012 the authors.