Microglial Stim1/Stim2 deletion reduces calcium signaling but promotes infarct expansion after ischemic stroke

Microglia respond to ischemic stroke with calcium transients carried by calcium release-activated calcium (CRAC) channels, gated by the endoplasmic reticulum sensors Stim1 and Stim2. Since CRAC signaling drives pro-inflammatory responses in immune cells, blocking it in microglia should protect the ischemic brain. We have examined this hypothesis in 15-month-old mice lacking Stim1 and Stim2 in microglia (Cx3cr1-CreERT2; Stim cKO). In vivo two-photon imaging confirmed that cKO microglia produced one-third smaller calcium transients during cortical spreading depolarizations. We then followed distal middle cerebral artery occlusion (dMCAo) with multiparametric MRI at 9.4 T. Six hours after occlusion, both the control and cKO genotypes demonstrated similar infarct size, edema, and diffusion, but lesion perfusion tended to be lower in cKO mice. Differences in tissue injury emerged later. Between 6 and 48 hours, the infarcts in control males did not grow, whereas infarcts in cKO males expanded 2.7-fold. At 48 hours, cKO males had 2.2-fold larger infarcts, while cKO females did not differ from controls. Moreover, cKO lesions showed a lower apparent diffusion coefficient, indicating more severe tissue injury. Neither hemispheric swelling nor cerebral arterial anatomy accounted for these differences. Contrary to our hypothesis, ablating microglial CRAC channels worsened stroke outcome. Microglial CRAC signaling may therefore protect threatened tissue in the first days after ischemia, possibly by sustaining its perfusion, and this role appears to outweigh its pro-inflammatory effects.