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

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.

Keywords

astrocyte / connexin 43 / fear memory retrieval / peroxisome proliferator-activated receptor gamma coactivator‑1α / posttraumatic stress disorder

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