4.7 Article

Indirect Effects of Halorhodopsin Activation: Potassium Redistribution, Nonspecific Inhibition, and Spreading Depolarization

期刊

JOURNAL OF NEUROSCIENCE
卷 43, 期 5, 页码 685-692

出版社

SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1141-22.2022

关键词

chloride; halorhodopsin; potassium; pyramidal cells; spreading depression

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The activation of halorhodopsin has significant effects on neighboring cells, including the redistribution of K+, rebound increase in K+ concentration, and cortical spreading depolarizations. This experimental model provides new insights into the understanding of these natural phenomena.
The movement of ions in and out of neurons can exert significant effects on neighboring cells. Here we report several experimentally important consequences of activation of the optogenetic chloride pump, halorhodopsin. We recorded extracellular K+ concentration ([K+](extra)) in neocortical brain slices prepared from young adult mice (both sexes) which express halorhodopsin in pyramidal cells. Strong halorhodopsin activation induced a pronounced drop in [K+](extra) that persisted for the duration of illumination. Pharmacological blockade of K+ channels reduced the amplitude of this drop, indicating that it represents K+ redistribution into cells during the period of hyperpolarization. Halorhodopsin thus drives the inward movement of both Cl- directly, and K+ secondarily. When the illumination period ended, a rebound surge in extracellular [K+] developed over tens of seconds, partly reflecting the previous inward redistribution of K+, but additionally driven by clearance of Cl- coupled to K+ by the potassium-chloride cotransporter, KCC2. The drop in [K+](extra) during light activation leads to a small (2-3 mV) hyperpolarization also of other cells that do not express halorhodopsin. Its activation therefore has both direct and indirect inhibitory effects. Finally, we show that persistent strong activation of halorhodopsin causes cortical spreading depolarizations (CSDs), both in vitro and in vivo. This novel means of triggering CSDs is unusual, in that the events can arise during the actual period of illumination, when neurons are being hyperpolarized and [K+](extra) is low. We suggest that this fundamentally different experimental model of CSDs will open up new avenues of research to explain how they occur naturally.

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