Involvement of NMDA receptors containing the GluN2C subunit in the psychotomimetic and antidepressant-like effects of ketamine

Ketamine produces rapid antidepressant effects but also perceptual disturbances similar to those caused by PCP. The brain networks involved are not fully understood, but both drugs activate thalamo-cortical networks by blocking NMDA receptors in the reticular thalamic nucleus. This study examined whether the GluN2C subunit of the NMDA receptor, densely expressed in the thalamus and cerebellum, mediates these effects using wild-type and GluN2C knockout mice of both sexes. GluN2C deletion dramatically reduced ketamine-induced circling behavior in both sexes, but the antidepressant-like effect was fully preserved. Some sex differences in c-fos expression and glutamate levels were observed. The GluN2C subunit may distinguish between ketamine's antidepressant and psychotomimetic actions, and cerebellar NMDA receptors may contribute to some behavioral effects.

Study at a glance

Abstract

Acute ketamine administration evokes rapid and sustained antidepressant effects in treatment-resistant patients. However, ketamine also produces transient perceptual disturbances similarly to those evoked by other non-competitive NMDA-R antagonists like phencyclidine (PCP). Although the brain networks involved in both ketamine actions are not fully understood, PCP and ketamine activate thalamo-cortical networks after NMDA-R blockade in GABAergic neurons of the reticular thalamic nucleus (RtN). Given the involvement of thalamo-cortical networks in processing sensory information, these networks may underlie psychotomimetic action. Since the GluN2C subunit is densely expressed in the thalamus, including the RtN, we examined the dependence of psychotomimetic and antidepressant-like actions of ketamine on the presence of GluN2C subunits, using wild-type and GluN2C knockout (GluN2CKO) mice. Likewise, since few studies have investigated ketamine’s effects in females, we used mice of both sexes. GluN2C deletion dramatically reduced stereotyped (circling) behavior induced by ketamine in male and female mice, while the antidepressant-like effect was fully preserved in both genotypes and sexes. Despite ketamine appeared to induce similar effects in both sexes, some neurobiological differences were observed between male and female mice regarding c-fos expression in thalamic nuclei and cerebellum, and glutamate surge in prefrontal cortex. In conclusion, the GluN2C subunit may discriminate between antidepressant-like and psychotomimetic actions of ketamine. Further, the abundant presence of GluN2C subunits in the cerebellum and the improved motor coordination of GluN2CKO mice after ketamine treatment suggest the involvement of cerebellar NMDA-Rs in some behavioral actions of ketamine.