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

Psilocybin rapidly reversed depressive-like behaviors in mice subjected to chronic restraint stress, an effect comparable to ketamine. Both drugs prevented stress-induced loss of astrocytes and reduced levels of the A1 astrocyte marker C3 protein in the prefrontal cortex. The active metabolite psilocin stimulated primary astrocyte activation, proliferation, and release of ATP, lactate, and glutamate, and improved mitochondrial function. Psilocin also reversed impairments caused by A1 astrocytes. Depleting astrocytes in the prelimbic region of the medial prefrontal cortex diminished psilocybin's antidepressant action in unstressed mice, suggesting astrocytes play a key role in the drug's effects.

Study at a glance

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.