Abolished ketamine effects on the spontaneous excitatory postsynaptic current of medial prefrontal cortex neurons in GluN2D knockout mice

Abstract

Ketamine, a non-competitive antagonist of the N-methyl-d-aspartate receptor (NMDAR), generates a rapidly-acting antidepressant effect. It exerts psychomimetic effects, yet demands a further investigation of its mechanism. Previous research showed that ketamine did no longer promote hyperlocomotion in GluN2D knockout (KO) mice, which is a subunit of NMDAR. In the present study, we tested whether GluN2D-containing NMDARs participate in the physiological changes in the medial prefrontal cortex (mPFC) triggered by ketamine. Sub-anesthetic dose of ketamine (25 mg/kg) elevated the frequency of spontaneous excitatory postsynaptic currents (sEPSC) in wild-type (WT) mice, but not in GluN2D KO mice, 1 h after the injection. The amplitude of sEPSC and paired-pulse ratio (PPR) were unaltered by ketamine in both WT and GluN2D KO mice. These findings suggest that GluN2D-containing NMDARs might play a role in the ketamine-mediated changes in glutamatergic neurons in mPFC and, presumably, in ketamine-induced hyperlocomotion.

Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments

“…These NMDAR subtypes are well-represented in interneuron populations ( 161 – 165 ), although they are present in fewer excitatory synapses than GluN2B or GluN2A. GluN2D knockout mice do not exhibit glutamatergic neuronal activation in response to ketamine ( 166 ). The GluN2D-prefering NMDAR antagonist, S-methadone ( 146 ), showed efficacy in a preclinical study ( 167 ), where it activated mTOR and induced synaptic regrowth.…”

Non-Opioid Anesthetics Addiction: A Review of Current Situation and Mechanism

“…In addition, repeated administration of ketamine significantly increased the expression of the GluN1 subunit gene and increased the polymorphism of the GluN2B gene [ 115 , 116 ]. Moreover, ketamine-induced hyperlocomotion and behavioral sensitization would be blocked by the knockout of the GluN2D gene, indicating that GluN2D plays a regulatory role in ketamine addiction [ 89 , 91 ].…”