Morphotype-specific calcium signaling in human microglia.

BACKGROUND: Key functions of Ca(2+) signaling in rodent microglia include monitoring the brain state as well as the surrounding neuronal activity and sensing the danger or damage in their vicinity. Microglial Ca(2+) dyshomeostasis is a disease hallmark in many mouse models of neurological disorders but the Ca(2+) signal properties of human microglia remain unknown. METHODS: We developed a novel genetically-encoded ratiometric Ca(2+) indicator, targeting microglial cells in the freshly resected human tissue, organotypically cultured tissue slices and analyzed in situ ongoing Ca(2+) signaling of decades-old microglia dwelling in their native microenvironment. RESULTS: The data revealed marked compartmentalization of Ca(2+) signals, with signal properties differing across the compartments and resident morphotypes. The basal Ca(2+) levels were low in ramified and high in ameboid microglia. The fraction of cells with ongoing Ca(2+) signaling, the fraction and the amplitude of process Ca(2+) signals and the duration of somatic Ca(2+) signals decreased when moving from ramified via hypertrophic to ameboid microglia. In contrast, the size of active compartments, the fraction and amplitude of somatic Ca(2+) signals and the duration of process Ca(2+) signals increased along this pathway.