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..., Detailed descriptions of data collection and analysis methods are provided in the associated article.
, # Astrocytic PERK deficiency drives prefrontal circuit dysfunction and depressive-like behaviors

Dataset DOI: [10.5061/dryad.mkkwh71dq](https://doi.org/10.5061/dryad.mkkwh71dq)

## Description of the data and file structure

This dataset contains the individual source data supporting figures and analyses in the associated article.

### Files and variables

**File:** SourceData_Fig_1.xlsx

**Description:** Source data for Figure 1, panels C, D, F–H, and J–K.

Sheet Fig. 1C: quantification of *GFAP* puncta number per astrocyte and *EIF2AK3* puncta number per *GFAP*^+^ astrocyte in control and MDD samples.

Sheet Fig. 1D: quantification of *EIF2AK3* puncta number in *SNAP25*^+^ neurons and *AIF1*^+^ microglia in control and MDD samples.

Sheet Fig. 1F: quantification of *Eif2ak3* puncta number in *S100β*^+^ astrocytes of WT mice treated with vehicle or corticosterone (CORT).

Sheet Fig. 1G: immunoblot analysis of PERK protein levels (fold change) in astrocytes isolated from the mouse mPFC...,