Astrocytic PERK deficiency drives prefrontal circuit dysfunction and depressive-like behaviors

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 Ca2+
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.