Sustained antidepressant actions of ketamine involve TAMM41-mediated transfer of astrocytic sigma-1 receptor to...

Several limitations such as delayed onset and insufficient efficacy exist in current antidepressant treatments, thereby driving the search for new therapeutic approaches. Ketamine produces a rapid and sustained antidepressant response, yet its molecular mechanisms remain elusive. Here, we elucidated that the transfer of sigma-1 receptor (S1R) from astrocytes to neurons was associated with ketamine's antidepressant effect. Mechanistically, we identified that ketamine activated the mitochondrial protein TAMM41 and then facilitated the transfer of astrocytic S1R via the TAMM41-cardiolipin-exosomes axis. Furthermore, conditional deletion of astrocytic TAMM41 exhibited depressive-like behaviors and abolished the sustained antidepressant effect of ketamine. Inspired by these findings of endogenous exosomes delivering S1R, we devised a strategy to engineer exosome-encapsulated S1R (S1R-EXOs) using exosomes released by human red blood cells and synthetic S1R mRNA. We found that exogenous S1R-EXOs effectively delivered S1R to neurons in S1R knockout mice. Finally, we verified that exogenous S1R-EXOs produced antidepressant-like effect. Our findings reveal that astrocytic TAMM41 underlies the sustained antidepressant effect of ketamine through exosomal delivery of S1R to neurons, offering potential for new strategies in depression treatment. Considering the advantages of human red blood cells and therapeutic mRNA, our results also provide a promising avenue that warrants further translational and clinical exploration.