Optogenetic determination of dynamic and cell-typespecific inhibitory reversal potentials

Item Type:	Article
Title:	Optogenetic determination of dynamic and cell-typespecific inhibitory reversal potentials
Creators Name:	Burman, R.J. and Diviney, T. and Călin, A. and Gothard, G. and Jouhanneau, J.S. and Poulet, J.F.A. and Sen, A. and Akerman, C.J.
Abstract:	The reversal potential refers to the membrane potential at which the net current flow through a channel reverses direction. The reversal potential is determined by transmembrane ion gradients and, in turn, determines how the channel’s activity will affect the membrane potential. Traditional investigation into the reversal potential of inhibitory ligand-gated ion channels (E(Inh)) has relied upon the activation of endogenous receptors, such as the GABA-A receptor (GABA(A)R). There are, however, challenges associated with activating endogenous receptors, including agonist delivery, isolating channel responses, and the effects of receptor saturation and desensitization. Here we demonstrate the utility of using a light-gated anion channel, stGtACR2, to probe E(Inh) in the rodent brain. Using mice of both sexes, we demonstrate that the properties of this optically activated channel make it a suitable proxy for studying GABA(A)R receptor mediated inhibition. We validate this agonist-independent optogenetic strategy in vitro and in vivo, and further show how it can accurately capture differences in E(Inh) dynamics following manipulations of endogenous ion fluxes. This allows us to explore distinct resting E(Inh) differences across genetically-defined neuronal subpopulations. Using this approach to challenge ion homeostasis mechanisms in neurons, we uncover cellspecific E(Inh) dynamics that are supported by the differential expression of endogenous ion handling mechanisms. Our findings therefore establish an effective optical strategy for revealing novel aspects of inhibitory reversal potentials, and thereby expand the repertoire of optogenetics.
Keywords:	Animals, Mice
Source:	Journal of Neuroscience
ISSN:	0270-6474
Publisher:	Society for Neuroscience
Page Range:	e1392232024
Date:	11 April 2024
Official Publication:	https://doi.org/10.1523/jneurosci.1392-23.2024
PubMed:	View item in PubMed

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