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 E

SUBMITTER: Chen K 

PROVIDER: S-EPMC12904067 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature