title: Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors.
abstract: 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 insertion of calcium (Ca(2+))-permeable GluA2-lacking receptors, little is known about the expression mechanism for altered NMDAR transmission. Combining ex vivo patch-clamp recordings, mouse genetics, and subcellular Ca(2+) imaging, we observe that cocaine drives the insertion of NMDARs that are quasi-Ca(2+)-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.
authors.affiliation: Department of Basic Neurosciences, Medical Faculty, University of Geneva, 1 rue Michel Servet, CH-1211 Geneva, Switzerland.
authors.forename: Tifei
authors.initials: T
authors.lastname: Yuan
authors.forename: Manuel
authors.initials: M
authors.lastname: Mameli
authors.forename: Eoin C
authors.initials: EC
authors.lastname: O'Connor
authors.forename: Eoin C
authors.initials: EC
authors.lastname: O' Connor
authors.forename: Partha Narayan
authors.initials: PN
authors.lastname: Dey
authors.forename: Chiara
authors.initials: C
authors.lastname: Verpelli
authors.forename: Carlo
authors.initials: C
authors.lastname: Sala
authors.forename: Isabel
authors.initials: I
authors.lastname: Perez-Otano
authors.forename: Christian
authors.initials: C
authors.lastname: Lüscher
authors.forename: Camilla
authors.initials: C
authors.lastname: Bellone
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009473:Neuronal Plasticity / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D034622:RNA Interference; D018091:Receptors, AMPA / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013238:Stereotaxic Techniques; D013569:Synapses / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D018765:Dopamine Uptake Inhibitors; C584082:GluN3A protein, mouse; C121001:NR2B NMDA receptor; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D003042:Cocaine; D002118:Calcium