Depression involves disruptions in the endoplasmic reticulum (ER) of serotonin neurons. In mice, artificially inducing ER stress in these neurons reduced Egr1-dependent serotonin activity and neurotransmission, leading to impaired neuroplasticity in forebrain regions and depressive-like behaviors. Ketamine reversed these effects by activating eIF2α signaling, which rapidly restored neuroplasticity. The findings identify ER stress in serotonin neurons as a cellular mechanism in depression and highlight eIF2α as a key target for ketamine's fast antidepressant action.
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.