Glutamate delta-1 receptor regulates cocaine-induced plasticity in the nucleus accumbens

Abstract

Cocaine exposure induces plasticity of glutamatergic synapses of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), which has been proposed to contribute to its addictive behavior. The mechanisms underlying cocaine-induced plasticity are not fully understood. The orphan glutamate delta-1 (GluD1) receptor is a member of the ionotropic glutamate receptor family but does not function as a typical ligand-gated ion channel. Instead it serves a synaptogenic function by interacting with presynaptic Neurexin protein. Recent neuroanatomical studies have demonstrated enriched expression of GluD1 in the NAc but its role in reward behavior, MSN function, and drug-induced plasticity remains unknown. Using a combination of constitutive and conditional GluD1 KO models, we evaluated the effect of GluD1 ablation on cocaine-conditioned place preference (CPP) and cocaine-induced structural and functional plasticity. GluD1 KO mice showed higher cocaine CPP. Selective ablation of GluD1 from striatal neurons but not cortico-limbic excitatory neurons reproduced higher CPP. Higher cocaine preference in GluD1 KO correlated with an increase in spine density, greater maturation of dendritic spines, and basally upregulated spine-regulating active cofilin. GluD1 loss did not affect basal excitatory neurotransmission or plasticity but masked the generation of cocaine-induced silent synapses. Finally, loss of GluD1 increased the GluN2B subunit contribution to NMDA receptor currents in MSNs and a partial agonist of GluN2B-containing NMDA receptors normalized the higher active cofilin and cocaine preference in GluD1 KO mice. Together, these findings demonstrate a critical role of GluD1 in controlling susceptibility to cocaine preference and cocaine-induced plasticity by modulating NMDA receptor subunit contribution.

More than Addiction—The Nucleus Accumbens Contribution to Development of Mental Disorders and Neurodegenerative Diseases

“…Results of animal studies showed that these changes depend on the level of AMPARs expression and the receptor’s subunit composition [ 21 ]. Furthermore, an increased expression of the orphan glutamate delta-1 receptor (GluD1R) has been reported in the NAc after cocaine administration [ 22 ]. GluD1R is a member of the ionotropic glutamate receptor family regarded as an important factor in the regulation of cocaine susceptibility.…”

Cryo-EM structures of the ionotropic glutamate receptor GluD1 reveal a non-swapped architecture

“…Unlike other iGluRs, Delta receptors do not generate ligand-gated currents [6][7][8] and are believed to exert their physiological functions via a non-canonical (metabotropic) pathway [9][10][11][12] . Dysfunction of GluD receptors is associated with social and cognitive deficits, 9,13 cerebellar long-term depression (LTD), [11][12]14 cerebellar ataxia and atrophy [15][16] and is also linked to retinal dystrophy, 17 schizophrenia, [18][19] and cocaine addiction 20 . The primary function of GluD receptors is believed to be their ability to act as a bidirectional synaptic organizer via trans-synaptic interactions at presynaptic termini mediated through neurexin and cerebellin, [21][22][23][24][25] and at postsynaptic sites via direct interactions with shank scaffold proteins [26][27] .…”

Discovery of a Role for Rab3b in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic Analysis

“…Studies in humans and non-human primates have established a relationship between cocaine sensitization with clinical symptomology ( Bradberry, 2008 ). Cocaine-induced behavioral sensitization is a measure of drug-induced plasticity, specifically adaptation of the mesocorticolimbic dopamine (DA) system ( Liu et al, 2018 ). Locomotion as a behavioral assay of cocaine use was employed to identify Cyfip2 ( Kumar et al, 2013 ) via quantitative trait locus (QTL) mapping in a reduced complexity cross, as a causative variant for acute and sensitized cocaine response phenotypes.…”