Microglia alter the threshold of spreading depolarization and related potassium uptake in the mouse brain

Abstract

Selective elimination of microglia from the brain was shown to dysregulate neuronal Ca2+ signaling and to reduce the incidence of spreading depolarization (SD) during cerebral ischemia. However, the mechanisms through which microglia interfere with SD remained unexplored. Here, we identify microglia as essential modulators of the induction and evolution of SD in the physiologically intact brain in vivo. Confocal- and super-resolution microscopy revealed that a series of SDs induced rapid morphological changes in microglia, facilitated microglial process recruitment to neurons and increased the density of P2Y12 receptors (P2Y12R) on recruited microglial processes. In line with this, depolarization and hyperpolarization during SD were microglia- and P2Y12R-dependent. An absence of microglia was associated with altered potassium uptake after SD and increased the number of c-fos-positive neurons, independently of P2Y12R. Thus, the presence of microglia is likely to be essential to maintain the electrical elicitation threshold and to support the full evolution of SD, conceivably by interfering with the extracellular potassium homeostasis of the brain through sustaining [K+]e re-uptake mechanisms.

TMEM16F Aggravates Neuronal Loss by Mediating Microglial Phagocytosis of Neurons in a Rat Experimental Cerebral Ischemia and Reperfusion Model

“…Microglia also play an important role in this process. PS-exposed neurons are recognized either via the opsonin MFG-E8 and vitronectin receptors on microglia ( 10 ) or by the opsonin Gas6 and MerTK (Mer receptor tyrosine kinase) receptors on microglia ( 8 , 9 , 55 ). It appears that inflammatory activation of microglia impairs their ability to discriminate between apoptotic and viable neurons for phagocytosis, resulting in phagoptosis during inflammation ( 56 ).…”

Neuronal gamma oscillations and activity‐dependent potassium transients remain regular after depletion of microglia in postnatal cortex tissue

“…These findings suggest that the ramified and widely nonreactive microglia are not involved in K + clearance and buffering during robust neuronal activation in situ, neither directly nor indirectly by modulating astrocyte functions (Larsen, Stoica, & MacAulay, 2016; Varga et al., 2020).…”

Microglia control cerebral blood flow and neurovascular coupling via P2Y12R-mediated actions

“…In studies investigating brain pH and DC potential, CCAo was performed by a mechanical occluder, which resulted in a larger (over 40%) and more abrupt CBF reduction, unexpectedly triggering SD, a large acidic pH shift and progressive oligaemia in the absence of microglia. Interestingly, we have previously reported altered extracellular potassium homeostasis after microglia depletion in vivo , with a lower initial SD threshold in the intact brain, but impaired SD induction after repeated SDs, or during hypoperfusion due to cerebral ischemia 21, 63 . In the presented study, microglia depleted mice immediately showed a robust, 80% drop in CBF during the first CCAo, followed by sustained impairment in CBF recovery, which was also seen in the milder CCAo model upon different microglia manipulations.…”