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.

Epac Signaling Is Required for Cocaine-Induced Change in AMPA Receptor Subunit Composition in the Ventral Tegmental Area

“…GluA2-lacking AMPARs exhibit higher single-channel conductance and calcium permeability than GluA2-containing AMPARs (Mameli et al, 2007). A cocaine-induced increase in GluA2-lacking AMPARs in the VTA may contribute to the increase in the AMPAR/NMDAR ratio (Ungless et al, 2001;Borgland et al, 2004;Bellone and Lüscher, 2006;Mameli et al, 2007Argilli et al, 2008) and LTP at hyperpolarizing membrane potentials (Mameli et al, 2011). Repeated cocaine injections render adaptions in the VTA persistent, which triggers adaptions downstream in the nucleus accumbens (Kourrich et al, 2007;Conrad et al, 2008;Huang et al, 2009;).…”

“…Dopamine D 1 and D 2 receptors are G-protein-coupled receptors, the activation of which leads to changes in intracellular cAMP levels (Neve et al, 2004;Anderson and Pierce, 2005;Tritsch and Sabatini, 2012). cAMP activates intracellular effectors: the classic protein kinase A (PKA) and the recently discovered exchange protein directly activated by cAMP (Epac;Cheng et al, 2008;Gloerich and Bos, 2010;Schmidt et al, 2013). PKA and its downstream effectors have been examined extensively in the context of drug addiction (Anderson and Pierce, 2005).…”

“…Epac2 is expressed predominately in the brain, whereas Epac1 is expressed ubiquitously in many tissues but its expression in the brain is very low (Kawasaki et al, 1998;de Rooij et al, 1998). Epac2 Ϫ/Ϫ mice exhibit deficits in social interaction and communication but normal locomotor activity and working and reference memory (Srivastava et al, 2012). There is also evidence for functional redundancy between Epac1 and Epac2, because Epac double knock-out mice (Epac Ϫ/Ϫ ) show deficits in hippocampal longterm potentiation (LTP), social interaction, and spatial learning and memory.…”

“…There is also evidence for functional redundancy between Epac1 and Epac2, because Epac double knock-out mice (Epac Ϫ/Ϫ ) show deficits in hippocampal longterm potentiation (LTP), social interaction, and spatial learning and memory. However, neither Epac1 Ϫ/Ϫ nor Epac2 Ϫ/Ϫ mice exhibit these phenotypes (Yang et al, 2012). Given its important roles in synaptic transmission in learning and memory, Epac is well positioned to regulate drug-induced synaptic plasticity and reinforcement learning.…”

“…However, how D 1 receptor activation leads to an increase in GluA2-lacking AMPARs remains poorly understood. Epac is a downstream effector of D 1 receptors (Woolfrey et al, 2009). Epac2 is coimmunoprecipitated with GluA2/3 but not with GluA1, and the selective Epac agonist 8-CPT-2Me-cAMP (8-CPT) induces removal of GluA2/3 AMPARs in cultured cortical neurons (Woolfrey et al, 2009).…”