Microglia promote remyelination independent of their role in clearing myelin debris.

Multiple sclerosis (MS) is an inflammatory disease characterized by myelin loss. While therapies exist to slow MS progression, no treatment currently exists for remyelination. Remyelination, linked to reduced disability in MS, relies on microglia and monocyte-derived macrophages (MDMs). This study aims to understand the role of microglia during remyelination by lineage tracing and depleting them. Microglial lineage tracing reveals that both microglia and MDMs initially accumulate, but microglia later dominate the lesion. Microglia and MDMs engulf equal amounts of inhibitory myelin debris, but after microglial depletion, MDMs compensate by engulfing more myelin debris. Microglial depletion does, however, reduce the recruitment and proliferation of oligodendrocyte progenitor cells (OPCs) and impairs their subsequent differentiation and remyelination. These findings underscore the essential role of microglia during remyelination and offer insights for enhancing this process by understanding microglial regulation of remyelination.

Orai, RyR, and IP3R channels cooperatively regulate calcium signaling in brain mid-capillary pericytes.

Pericytes are multifunctional cells of the vasculature that are vital to brain homeostasis, yet many of their fundamental physiological properties, such as Ca2+ signaling pathways, remain unexplored. We performed pharmacological and ion substitution experiments to investigate the mechanisms underlying pericyte Ca2+ signaling in acute cortical brain slices of PDGFRß-Cre::GCaMP6f mice. We report that mid-capillary pericyte Ca2+ signalling differs from ensheathing type pericytes in that it is largely independent of L- and T-type voltage-gated calcium channels. Instead, Ca2+ signals in mid-capillary pericytes were inhibited by multiple Orai channel blockers, which also inhibited Ca2+ entry triggered by endoplasmic reticulum (ER) store depletion. An investigation into store release pathways indicated that Ca2+ transients in mid-capillary pericytes occur through a combination of IP3R and RyR activation, and that Orai store-operated calcium entry (SOCE) is required to sustain and amplify intracellular Ca2+ increases evoked by the GqGPCR agonist endothelin-1. These results suggest that Ca2+ influx via Orai channels reciprocally regulates IP3R and RyR release pathways in the ER, which together generate spontaneous Ca2+ transients and amplify Gq-coupled Ca2+ elevations in mid-capillary pericytes. Thus, SOCE is a major regulator of pericyte Ca2+ and a target for manipulating their function in health and disease.