Astrocytic pleiotrophin deficiency in the prefrontal cortex contributes to stress-induced depressive-like responses in male mice

Astrocytes are closely linked to depression, and the prefrontal cortex (PFC) is an important brain region involved in major depressive disorder (MDD). However, the underlying mechanism by which astrocytes within PFC contribute to MDD remains unclear. Using single-nucleus RNA sequencing analyses, we show a significant reduction in astrocytes and attenuated pleiotrophin-protein tyrosine phosphatase receptor type Z1 (PTN-PTPRZ1) signaling in astrocyte-to-excitatory neuron communication in the PFC of male MDD patients. We find reduced astrocytes and PTN in the dorsomedial PFC of male mice with depression induced by chronic restraint and social defeat stress. Knockdown of astrocytic PTN induces depression-related responses, which is reversed by exogenous PTN supplementation or overexpression of astrocytic PTN. The antidepressant effects exerted by astrocytic PTN require interaction with PTPRZ1 in excitatory neurons, and PTN-PTPRZ1 activates the AKT signaling pathway to regulate depression-related responses. Our findings indicate the PTN-PTPRZ1-AKT pathway may be a potential therapeutic target for MDD.