Membrane Associated RNA-Containing Vesicles Regulate Cortical Astrocytic Microdomain Calcium Transients in Awake Ischemic Stroke Mice

Abstract

Astrocytic processes minutely regulate neuronal activity via tripartite synaptic structures. The precision-tuning of the function of astrocytic processes is garnering increasing attention because of its significance in promoting brain repair following ischemic stroke. Microdomain calcium (Ca²⁺) transients in astrocytic processes are pivotal for the functional regulation of these processes. However, the understanding of the alterations and regulatory mechanism of microdomain Ca²⁺ transients during stroke remains limited. In the present study, a fast high-resolution, miniaturized two-photon microscopy is used to show that the levels of astrocytic microdomain Ca²⁺ transients are significantly reduced in the peri-infarct area of awake ischemic stroke mice. This finding correlated with the behavioral deficits shown by these mice under freely-moving conditions. Mitochondrial Ca²⁺ activity is an important factor driving the microdomain Ca²⁺ transients. DEAD Box 1 (DDX1) bound to circSCMH1 (a circular RNA involved in vascular post-stroke repair) facilitates the formation of membrane-associated RNA-containing vesicles (MARVs) and enhances the activity of astrocytic microdomain Ca²⁺ transients, thereby promoting behavioral recovery. These results show that targeting astrocytic microdomain Ca²⁺ transients is a potential therapeutic approach in stroke intervention.

Keywords: astrocytic microdomain calcium transients; circSCMH1; ischemic stroke; membrane associated RNA‐containing vesicles; mitochondria.