The astrocytes in the prefrontal cortex contribute to the rapid antidepressant-like effects of psilocybin in the chronic restraint stress mouse model

Abstract

Psilocybin showed a rapid antidepressant response in several clinical trials, which offers new hope for treating depression. Astrocytes were associated with the etiology of depression and might contribute to the onset of psilocybin. In this study, we investigated the fast antidepressant effect of psilocybin and tested variations of GFAP (astrocytic markers) and C3 protein (markers of A1 astrocyte) expression after psilocybin treatment in the chronic restraint stress (CRS) mouse model. We next defined the modulating impact of psilocin (psilocybin's main active metabolite) on primary astrocytes as well as A1 astrocytes in vitro. The depletion of astrocytes was achieved by AAV injection to further verify the astrocytic role underlying the action of psilocybin. Psilocybin and ketamine (positive control) rapidly reversed the depressive-like behaviors in the CRS mice. Both psilocybin and ketamine inhibited the CRS-induced astrocytic loss and increased C3 protein in the prefrontal cortex (PFC). Psilocin up-regulated the activation and proliferation of primary astrocytes, and strengthened astrocytic ATP/lactate/glutamate release and mitochondrial function. Psilocin reversed A1 astrocyte-induced impairments in ATP/lactate/glutamate release and mitochondrial function. In vivo, depletion of astrocytes in the prelimbic (PrL) region of mPFC might affect the antidepressant action of psilocybin in unstressed mice. Our findings might be significant for a better understanding of astrocytic mechanisms in the action of psilocybin.