Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models.
Neuropharmacology August 1, 2022 Mireia Tarrés-Gatius, Ximena López-Hill, Lluis Miquel-Rio et al.
Non-competitive NMDA receptor antagonists like PCP and MK-801 produce schizophrenia-like effects, but the specific receptor subunits and brain regions involved are unclear. Using GluN2C knockout mice, the authors found that deleting the GluN2C subunit reduced stereotyped behaviors such as circling, rearing, and ataxia signs induced by PCP and MK-801, indicating better motor coordination. However, other motor effects and sensorimotor gating deficits (pre-pulse inhibition) remained unchanged. PCP and MK-801 activated c-fos in thalamo-cortical networks but reduced it in the cerebellum, with differences between genotypes matching motor coordination changes. Resting-state fMRI showed enhanced cortico-thalamic-cerebellar connectivity in knockout mice that was less disrupted by MK-801. Thus, GluN2C-containing NMDA receptors in cerebellar circuits mediate some motor incoordination effects but not sensorimotor gating deficits.