(2R, 6R)-hydroxynorketamine alleviates postictal depression induced by pilocarpine through modulating LRP4 expression in hippocampal astrocytes.
Epilepsy & behavior : E&B March 1, 2025 Meiying Zhang, Liting Zheng, Jixing Chen et al.
Depression-like behavior in a mouse model of epilepsy does not appear immediately after a seizure but develops within one week and persists for over two weeks. This corresponds with a significant drop in hippocampal LRP4 expression one day after status epilepticus, which partially recovers but remains low through day 14. Treatment with (2R, 6R)-hydroxynorketamine ((2R, 6R)-HNK), a ketamine metabolite, alleviates depressive-like behaviors within one day and continues for up to seven days, while reducing LRP4 expression in hippocampal astrocytes initially and then increasing it within a week. Overexpressing LRP4 in hippocampal astrocytes accelerated the onset of depressive-like behaviors and blocked the antidepressant effects of (2R, 6R)-HNK, suggesting that (2R, 6R)-HNK alleviates postictal depression through stage-specific modulation of LRP4 in astrocytes.