Ketamine, a rapid antidepressant, works by blocking N-methyl-d-aspartate receptors (NMDARs) specifically in the lateral habenula (LHb) of the brain, not in the hippocampus. In depressive-like mice, this regional selectivity depends on local neural activity and the availability of extrasynaptic NMDARs. Activating the hippocampus or inactivating the LHb reversed this sensitivity. Removing NMDARs from the LHb prevented ketamine's antidepressant effects and blocked the drug-induced rise in serotonin and brain-derived neurotrophic factor in the hippocampus. Identifying this primary brain target should help design more precise antidepressant treatments.
Esketamine improves cognitive impairments and alleviates neuronal damage in mice with sepsis-associated encephalopathy by inhibiting microglia-mediated neuroinflammation. The beneficial effects of Esketamine on microglia and cognitive behavior were counteracted by the BDNF receptor antagonist K252a in both in vivo and in vitro experiments. These results suggest that Esketamine inhibits microglia-mediated neuroinflammation by activating the BDNF pathway, thereby mitigating neuronal damage and cognitive dysfunction associated with sepsis-associated encephalopathy.
In a mouse model of depression induced by chronic social defeat stress, susceptible mice showed reduced social interaction, lower sucrose preference, decreased NRG1 protein expression in the prefrontal cortex, and increased immobility time compared to controls. A subanesthetic dose of esketamine increased NRG1 expression in the prefrontal cortex within 30 minutes and improved social interaction and reduced immobility at both 30 minutes and 24 hours post-injection. No significant changes were observed in GAD67 or ErbB4 expression. Esketamine may rapidly improve depressive-like behavior by regulating the NRG1-ErbB4 signaling pathway.