Spreading depolarization in the brain of Drosophila is induced by inhibition of the Na+/K+-ATPase and mitigated by a decrease in activity of protein kinase G

Spreading depolarization (SD) is characterized by a massive redistribution of ions accompanied by an arrest in electrical activity that slowly propagates through neural tissue. It has been implicated in numerous human pathologies including migraine, stroke and traumatic brain injury and thus elucidating control mechanisms underlying the phenomenon could have many health benefits. Here we demonstrate the occurrence of SD in the brain of Drosophila melanogaster providing a model system whereby cellular mechanisms can be dissected using molecular genetic approaches. Propagating waves of SD were reliably induced by disrupting the extracellular potassium concentration ([K⁺]_o) either directly or by inhibition of the Na⁺/K⁺-ATPase with ouabain. The disturbance was monitored by recording the characteristic surges in [K⁺]_o using K⁺-sensitive microelectrodes or by monitoring brain activity by measuring direct current (DC) potential. Using wild-type flies we show that young adults are more resistant to SD compared to older adults, evidenced by shorter bouts of SD activity and attenuated [K⁺]_o disturbances. Furthermore, we show that the susceptibility to SD differs between wild-type flies and w1118 mutants demonstrating that our ouabain-model is influenced by genetic strain. Lastly, flies with low levels of protein kinase G (PKG) had increased latencies to onset of both ouabain-induced SD and anoxic depolarization compared to flies with higher levels. Our findings implicate the PKG pathway as a modulator of SD in the fly brain and given the conserved nature of the signalling pathway it could likely play a similar role during SD in the mammalian CNS.

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