# Peroxisome Proliferator‑Activated Receptor Gamma Coactivator‑1α Deficiency in Hippocampal Astrocytes Underlies Enhanced Fear Memory Retrieval in Male Posttraumatic Stress Disorder Model Mice

## TL;DR

Reduced PGC-1α in astrocytes of PTSD mice impairs brain communication, leading to stronger fear memories, which can be reversed with treatments targeting these cells.

## Contribution

Identifies astrocytic PGC-1α/CX43 as a novel regulatory axis in PTSD-related fear memory retrieval.

## Key findings

- PGC-1α deficiency in hippocampal astrocytes correlates with enhanced fear memory retrieval in PTSD model mice.
- Chemogenetic activation of astrocytes or PGC-1α agonists rescues CX43 expression and normalizes fear behavior.
- Pharmacological inhibition of CX43 gap junctions mimics the pro-fear effects of PGC-1α deficiency.

## Abstract

Peroxisome proliferator‑activated receptor gamma coactivator‑1α (PGC‑1α), a key metabolic regulator, is implicated in astrocyte function, but its specific role during fear memory retrieval and in posttraumatic stress disorder (PTSD) pathogenesis remains unclear. Here, using the single‐prolonged stress mice model, we demonstrated a significant downregulation of PGC‑1α specifically within hippocampal astrocytes, concomitant with reduced astrocyte density, attenuated intracellular Ca2
+ signaling, and impaired activity‑dependent ATP release. Targeted knockdown of hippocampal astrocytic PGC‑1α in vivo was sufficient to potentiate fear memory retrieval. This behavioral enhancement was associated with a loss of complex astrocyte morphology, further suppression of ATP release, aberrant hippocampal neuronal activity, and a marked decrease in connexin 43 (CX43) expression. Notably, pharmacological inhibition of CX43‑based gap junctions mimicked this pro‑fear phenotype in control animals. Conversely, interventions either via chemogenetic activation of astrocytes or administration of PGC‑1α agonists effectively normalized fear memory responses and rescued CX43 levels in PTSD mice. Crucially, the therapeutic benefit of chemogenetic astrocyte activation was abolished when PGC‑1α was concomitantly knocked down. Collectively, our results demonstrate that PGC‐1α deficiency in hippocampal astrocytes underlies enhanced fear memory retrieval in PTSD model mice, highlighting the potential of astrocyte‑targeted strategies for preventing and treating PTSD.

PGC‑1α downregulation in hippocampal astrocytes disrupts ATP release and reduces connexin 43 (CX43) expression, impairing neuro‑glial communication. This promotes enhanced fear memory retrieval in PTSD. Chemogenetic activation of astrocytes or PGC‑1α agonist treatment rescues both CX43 expression and fear behavior, identifying astrocytic PGC‑1α/CX43 as a key regulatory axis and potential target for PTSD intervention.