Healthy Brain Aging Modifies Microglial Calcium Signaling In Vivo.

Brain aging is characterized by a chronic, low-grade inflammatory state, promoting deficits in cognition and the development of age-related neurodegenerative diseases. Malfunction of microglia, the brain-resident immune cells, was suggested to play a critical role in neuroinflammation, but the mechanisms underlying this malfunctional phenotype remain unclear. Specifically, the age-related changes in microglial Ca signaling, known to be linked to its executive functions, are not well understood. Here, using in vivo two-photon imaging, we characterize intracellular Ca signaling and process extension of cortical microglia in young adult (2⁻4-month-old), middle-aged (9⁻11-month-old), and old (18⁻21-month-old) mice. Our data revealed a complex and nonlinear dependency of the properties of intracellular Ca signals on an animal's age. While the fraction of cells displaying spontaneous Ca transients progressively increased with age, the frequencies and durations of the spontaneous Ca transients followed a bell-shaped relationship, with the most frequent and largest Ca transients seen in middle-aged mice. Moreover, in old mice microglial processes extending toward an ATP source moved faster but in a more disorganized manner, compared to young adult mice. Altogether, these findings identify two distinct phenotypes of aging microglia: a reactive phenotype, abundantly present in middle-aged animals, and a dysfunctional/senescent phenotype ubiquitous in old mice.