Experimental cortical spreading depression induces NMDA receptor dependent potassium currents in microglia

Abstract

Cortical spreading depression (CSD) is a propagating event of neuronal depolarization, which is considered as the cellular correlate of the migraine aura. It is characterized by a change in the intrinsic optical signal and by a negative DC potential shift. Microglia are the resident macrophages of the CNS and act as sensors for pathological changes. In the present study, we analyzed whether microglial cells might sense CSD by recording membrane currents from microglia in acutely isolated cortical mouse brain slices during an experimentally induced CSD. Coincident with the change in the intrinsic optical signal and the negative DC potential shift we recorded an increase in potassium conductance predominantly mediated by K+ inward rectifier (Kir)2.1, which was blocked by the NMDA receptor antagonist D-AP5. Application of NMDA and an increase in extracellular K+ mimics the CSD-induced Kir activation. Application of D-AP5, but not the purinergic receptor antagonist RB2, blocks the NMDA-induced Kir activation. The K+ channel blocker Ba2+ blocks both the CSD-and the NMDA-triggered increase in Kir channel activity. In addition, we could confirm previous findings that microglia in the adult brain do not express functional NMDA receptors by recording from microglia cultured from adult brain. From these observations we conclude that CSD activates neuronal NMDA receptors, which lead to an increase in extracellular [K+] resulting in the activation of Kir channel activity in microglia.