Subicular Astrocytes Govern Seizure-Impaired Fear Memory

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 Ca²⁺ 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 Ca²⁺-dependent gliotransmitter adenosine-mediated inhibition through A₁ 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 Ca²⁺-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.