(2R, 6R)-hydroxynorketamine alleviates postictal depression induced by pilocarpine through modulating LRP4 expression in hippocampal astrocytes

Postictal depression is a common comorbidity in epilepsy, yet effective treatments remain limited. While ketamine is well-known for its antidepressant properties, its role in postictal depression has not been thoroughly investigated. In this study, we utilized a pilocarpine-induced status epilepticus (SE) mouse model and found that depression-like behavior does not appear within a day after SE but develops within one week and persists for over two weeks. We also observed a significant reduction in hippocampal LRP4 expression one day after SE. However, despite partial recovery over the next seven days, LRP4 levels remained markedly lower through day 14, correlating with the onset and persistence of postictal depression. These findings suggest that SE-induced modulation of LRP4 expression plays distinct roles at different stages of postictal depression. Furthermore, treatment with (2R, 6R)-hydroxynorketamine ((2R, 6R)-HNK), a ketamine metabolite that lacks dissociative and addictive properties while retaining strong antidepressant-like effects, significantly alleviated depressive-like behaviors and reduced LRP4 expression in hippocampal astrocytes within one day of administration. This treatment continued to alleviate depressive-like behaviors for up to seven days, while notably increasing Lrp4 levels within one week. To further investigate the role of LRP4, we generated astrocyte-specific LRP4 overexpression mice by stereotactically injecting an Lrp4 OE adenovirus with the gfaABC1D promoter, driving astrocyte-specific expression, into the molecular layer (ML) of the hippocampus. LRP4 overexpression in hippocampal astrocytes accelerated the onset of depressive-like behaviors and abolished the antidepressant effects of (2R, 6R)-HNK. These findings indicate that (2R, 6R)-HNK alleviates postictal depression induced by pilocarpine through stage-specific modulation of LRP4 expression in hippocampal astrocytes. This research provides novel insights into potential therapeutic targets for managing postictal depression.