Expression of Cocaine-Evoked Synaptic Plasticity by GluN3A-Containing NMDA Receptors

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• 作者：Tifei Yuan ; Manuel Mameli ; Eoin聽C. O鈥櫬燙onnor ; Partha聽Narayan Dey ; Chiara Verpelli ; Carlo Sala ; Isabel Perez-Otano ; Christian L眉scher ; Camilla Bellone
• 刊名：Neuron
• 出版年：20 November, 2013
• 年：2013
• 卷：80
• 期：4
• 页码：1025-1038
• 全文大小：1982 K

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Summary

Drug-evoked synaptic plasticity in the mesolimbic dopamine (DA) system reorganizes neural circuits that may lead to addictive behavior. The first cocaine exposure potentiates AMPAR excitatory postsynaptic currents (EPSCs) onto DA neurons of the VTA but reduces the amplitude of NMDAR-EPSCs. While plasticity of AMPAR transmission is expressed by聽insertion of calcium (Ca²⁺)-permeable GluA2-lacking receptors, little is known about the expression聽mechanism for altered NMDAR transmission. Combining ex聽vivo patch-clamp recordings, mouse genetics, and subcellular Ca²⁺ imaging, we observe that cocaine drives the insertion of NMDARs that are quasi-Ca²⁺-impermeable and contain GluN3A and GluN2B subunits. These GluN3A-containing NMDARs appear necessary for the expression of cocaine-evoked plasticity of AMPARs. We identify an mGluR1-dependent mechanism to remove these noncanonical NMDARs that requires Homer/Shank interaction and protein synthesis. Our data provide insight into the early cocaine-driven reorganization of glutamatergic transmission onto DA neurons and offer GluN3A-containing NMDARs as new targets in drug addiction.