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KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels

67 Pages Posted: 15 Nov 2018 Sneak Peek Status: Under Review

See all articles by Marie Goutierre

Marie Goutierre

French Institute of Health and Medical Research (INSERM) - UMR-S 839; Université Paris I Panthéon-Sorbonne; Institut du Fer à Moulin

Sana Al Awabdh

French Institute of Health and Medical Research (INSERM) - UMR-S 839; Université Paris I Panthéon-Sorbonne; Institut du Fer à Moulin

Emeline François

French Institute of Health and Medical Research (INSERM) - UMR-S 839; Université Paris I Panthéon-Sorbonne; Institut du Fer à Moulin

Daniel Gomez-Dominguez

Consejo Superior de Investigaciones Científicas - Instituto Cajal

Theano Irinopoulou

French Institute of Health and Medical Research (INSERM) - UMR-S 839; Université Paris I Panthéon-Sorbonne; Institut du Fer à Moulin

Liset Menendez de la Prida

Consejo Superior de Investigaciones Científicas - Instituto Cajal

Jean Christophe Poncer

French Institute of Health and Medical Research (INSERM) - UMR-S 839; Université Paris I Panthéon-Sorbonne; Institut du Fer à Moulin

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Abstract

The K /Cl− co-transporter KCC2 (SLC12A5) regulates neuronal transmembrane chloride gradients and thereby controls GABA signaling in the brain. KCC2 downregulation is observed in several neurological and psychiatric disorders including epilepsy, neuropathic pain and autism spectrum disorders. Paradoxical, excitatory GABA signaling is usually assumed to contribute to abnormal network activity underlying the pathology. We tested this hypothesis and explored the functional impact of chronic KCC2 downregulation in the rat dentate gyrus. Although the reversal potential of GABAA receptor currents was depolarized in KCC2 knockdown neurons, this shift was fully compensated by depolarization of their resting membrane potential. This effect was due to downregulation of Task-3 leak potassium channels that we show require KCC2 for membrane trafficking. Increased neuronal excitability upon KCC2 suppression altered dentate gyrus rhythmogenesis that could be normalized by chemogenetic hyperpolarization. Our data reveal KCC2 downregulation engages complex synaptic and cellular alterations beyond GABA signaling that concur to perturb network activity, thus offering novel targets for therapeutic intervention.

Suggested Citation

Goutierre, Marie and Awabdh, Sana Al and François, Emeline and Gomez-Dominguez, Daniel and Irinopoulou, Theano and Menendez de la Prida, Liset and Poncer, Jean Christophe, KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels (November 14, 2018). Available at SSRN: https://ssrn.com/abstract=3284450 or http://dx.doi.org/10.2139/ssrn.3284450
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Marie Goutierre

French Institute of Health and Medical Research (INSERM) - UMR-S 839

Paris
France

Université Paris I Panthéon-Sorbonne

17, rue de la Sorbonne
Paris, IL 75005
France

Institut du Fer à Moulin

Paris, F75005
France

Sana Al Awabdh

French Institute of Health and Medical Research (INSERM) - UMR-S 839

Paris
France

Université Paris I Panthéon-Sorbonne

17, rue de la Sorbonne
Paris, IL 75005
France

Institut du Fer à Moulin

Paris, F75005
France

Emeline François

French Institute of Health and Medical Research (INSERM) - UMR-S 839

Paris
France

Université Paris I Panthéon-Sorbonne

17, rue de la Sorbonne
Paris, IL 75005
France

Institut du Fer à Moulin

Paris, F75005
France

Daniel Gomez-Dominguez

Consejo Superior de Investigaciones Científicas - Instituto Cajal

Ave Doctor Arce 37
Madrid, E-28002
Spain

Theano Irinopoulou

French Institute of Health and Medical Research (INSERM) - UMR-S 839

Paris
France

Université Paris I Panthéon-Sorbonne

17, rue de la Sorbonne
Paris, IL 75005
France

Institut du Fer à Moulin

Paris, F75005
France

Liset Menendez de la Prida

Consejo Superior de Investigaciones Científicas - Instituto Cajal ( email )

Ave Doctor Arce 37
Madrid, E-28002
Spain

Jean Christophe Poncer (Contact Author)

French Institute of Health and Medical Research (INSERM) - UMR-S 839 ( email )

Paris
France

Université Paris I Panthéon-Sorbonne ( email )

17, rue de la Sorbonne
Paris, IL 75005
France

Institut du Fer à Moulin ( email )

Paris, F75005
France