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

Dániel P. Varga, Ákos Menyhárt, Balázs Pósfai, Eszter Császár, Nikolett Lénárt, Csaba Cserép, Barbara Orsolits, Bernadett Martinecz, Tamás Szlepák, Ferenc Bari, Eszter Farkas, Ádám Dénes

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalJournal of Cerebral Blood Flow and Metabolism
DOIs
Publication statusAccepted/In press - Jan 1 2020

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Keywords

  • Microglia
  • P2Y12 receptor
  • extracellular potassium clearance
  • inflammation
  • spreading depolarization

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this

Varga, D. P., Menyhárt, Á., Pósfai, B., Császár, E., Lénárt, N., Cserép, C., Orsolits, B., Martinecz, B., Szlepák, T., Bari, F., Farkas, E., & Dénes, Á. (Accepted/In press). Microglia alter the threshold of spreading depolarization and related potassium uptake in the mouse brain. Journal of Cerebral Blood Flow and Metabolism. https://doi.org/10.1177/0271678X19900097