NR2B Signaling Regulates the Development of Synaptic AMPA Receptor Current

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Abstract
The postnatal maturation of glutamatergic synapses involves a change in composition and functional contribution of postsynaptic receptors. Developing cortical synapses are dominated by NMDA receptors (NMDARs) containing NR2B subunits and are characterized by a low ratio of AMPA/NMDA receptor-mediated current. Synapse maturation is marked by the incorporation of NR2A-containing NMDA receptors and an increase in the AMPA/NMDA current ratio. We show here that NMDARs containing the NR2B subunit regulate glutamatergic transmission at developing synapses by negatively influencing the synaptic incorporation of AMPA receptors (AMPARs). Genetic removal of NR2B leads to increased surface expression and synaptic localization of AMPA receptor subunits and a corresponding increase in AMPAR-mediated synaptic current. Enrichment of synaptic AMPARs, in the absence of NR2B signaling, is associated with increased levels of transmembrane AMPAR regulatory protein (TARP) expression and is blocked by expression of a dominant-negative TARP construct (γ-2ΔC). These observations suggest that NR2B signaling limits AMPA receptor incorporation at developing synapses by negatively regulating TARP expression and provide a mechanism to explain the maintenance of low AMPA/NMDA ratio at immature glutamatergic synapses.