STIM1‐Dependent Calcium Signaling in Astrocytes Controls Glutamate Accumulation and Ischemic Brain Injury During Acute Stroke in Mice

Astrocytes critically influence ischemic stroke outcomes through calcium signaling-dependent mechanisms, which can be both beneficial and detrimental. Stromal interaction molecule 1 (STIM1), a key regulator of store-operated calcium entry, has emerged as an essential mediator of intracellular calcium dynamics in astrocytes, yet its role in acute stroke remains largely unknown. Here, we demonstrate that conditional knockout of astrocytic STIM1 in mice dramatically reduces infarct volume and improves neurological function following ischemic stroke. In vivo two-photon imaging revealed that astrocytic STIM1 knockout reduces the amplitude and duration of both spreading depolarization-associated and spontaneous calcium transients during acute ischemia. The reduction of these transients was highly correlated with improved neurological outcomes. Furthermore, the astrocytic STIM1 knockout mitigated excitotoxic stress by accelerating glutamate clearance and reducing total glutamate burden during ischemic stroke. Our findings establish astrocytic STIM1 as a critical regulator of calcium and glutamate dynamics during ischemic stroke, and therefore, targeting astrocytic STIM1 represents a promising therapeutic avenue for alleviating ischemic brain damage by reducing calcium overload and glutamate excitotoxicity.