Subicular Astrocytes Govern Seizure‐Impaired Fear Memory

Abstract The mechanisms underlying seizure‐associated cognitive impairment remain incompletely characterized. Emerging evidence positions the subiculum, a hippocampal output hub critically involved in both epileptic seizure and cognitive performance, as a putative nexus for this comorbidity. Here, it is demonstrated that astrocytic activation in the subiculum mediates seizure‐induced fear memory deficits. Subicular astrocytes dynamically respond to conditioned fear memory learning, acting as a “scavenger” for the inhibition of context memory. Seizure activity hyperactivates these leaning‐associated astrocytes and amplifies their engagement during fear processing. Suppression of subicular astrocyte Ca ²⁺ signaling fully rescues seizure‐induced fear memory deficits, while Gq pathway activation in the subicular astrocytes replicates cognitive impairment. Mechanistically, this seizure‐induced astrocyte dysregulation specifically involves Ca ²⁺ ‐dependent gliotransmitter adenosine‐mediated inhibition through A ₁ receptors, reducing local neuronal excitability during fear processing. Collectively, these findings identify subicular astrocytes as critical modulators of seizure‐associated cognitive dysfunction, operating through a Ca ²⁺ ‐dependent adenosine‐linked pathway that disrupts neural circuit homeostasis. This work highlights the potential for astrocyte‐targeted interventions as a therapeutic strategy for seizure‐related memory disorders.