Astrocytic PERK Deficiency Drives Prefrontal Circuit Dysfunction and Depressive‐Like Behaviors

Abstract Major depressive disorder (MDD) is associated with dysfunction in prefrontal cortex (PFC) circuits, yet the glial mechanisms underlying these abnormalities remain unclear. Here, downregulation of the endoplasmic reticulum (ER) stress sensor PERK in PFC astrocytes is identified as a mechanistic contributor to depression‐related phenotypes. PERK expression is markedly reduced in PFC astrocytes from individuals with MDD and in two chronic‐stress mouse models. Astrocyte‐specific PERK deletion in stress‐naïve mice is sufficient to induce robust depressive‐like behaviors and widespread PFC circuit pathology, including dendritic spine loss, pyramidal neuron hypoactivity, and weakened functional connectivity. Mechanistically, PERK‐deficient astrocytes display reduced Nrf2 abundance, dysregulated ER and cytosolic Ca ²⁺ dynamics, and decreased expression of the synaptogenic protein thrombospondin‐1 (TSP1). Restoring astrocytic TSP1 via a blood‐brain barrier‐penetrant adeno‐associated virus rescues PFC circuit function and reverses depressive‐like behaviors. These findings establish astrocytic PERK deficiency as a sufficient driver of synaptic and network dysfunction underlying depressive phenotypes and highlight astrocyte‐directed TSP1 augmentation as a potential therapeutic strategy for MDD.