Astrocytic Pleiotrophin Deficiency In The Prefrontal Cortex Contributes To Stressinduced Depressivelike Responses In Male Mice Dongmei Chi Kun Zhang Jianxing Zhang Zhaoli He Hongxia Zhou Wan Huang Yang Liu Jingxiu Huang Weian Zeng Xiaohui Bai Chaopeng Ou Handong Ouyang by Dongmei Chi & Kun Zhang & Jianxing Zhang & Zhaoli He & Hongxia Zhou & Wan Huang & Yang Liu & Jingxiu Huang & Weian Zeng & Xiaohui Bai & Chaopeng Ou & Handong Ouyang 101038/S41467025579241 instant download after payment.

Wan Huang 1, Yang Liu2, Jingxiu Huang1, Weian Zeng1, Xiaohui Bai 3 ,Chaopeng Ou 1 & Handong Ouyang 1Astrocytes are closely linked to depression, and the prefrontal cortex (PFC) isan 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 attenuatedpleiotrophin-protein tyrosine phosphatase receptor type Z1 (PTN-PTPRZ1)signaling in astrocyte-to-excitatory neuron communication in the PFC of maleMDD patients. We find reduced astrocytes and PTN in the dorsomedial PFC ofmale mice with depression induced by chronic restraint and social defeatstress. Knockdown of astrocytic PTN induces depression-related responses,which is reversed by exogenous PTN supplementation or overexpression ofastrocytic PTN. The antidepressant effects exerted by astrocytic PTN requireinteraction with PTPRZ1 in excitatory neurons, and PTN-PTPRZ1 activates theAKT signaling pathway to regulate depression-related responses. Our findingsindicate the PTN-PTPRZ1-AKT pathway may be a potential therapeutic targetfor MDD.