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J Neurosci. 2015 May 27;35(21):8291-6. doi: 10.1523/JNEUROSCI.5205-14.2015.

Selective inhibition of KCC2 leads to hyperexcitability and epileptiform discharges in hippocampal slices and in vivo.

Author information

1
Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111, Department of Biosciences, University of Helsinki, 00014 Helsinki, Finland.
2
AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Boston, Massachusetts 02111.
3
Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.
4
AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Boston, Massachusetts 02111, AstraZeneca Neuroscience iMED, Cambridge, Massachusetts 02139, and.
5
Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111, AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Boston, Massachusetts 02111, Department of Neuroscience, Physiology and Pharmacology, University College, London, WC1E 6BT, United Kingdom Tarek.Deeb@tufts.edu Stephen.Moss@tufts.edu.
6
AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Boston, Massachusetts 02111, Tarek.Deeb@tufts.edu Stephen.Moss@tufts.edu.

Abstract

GABA(A) receptors form Cl(-) permeable channels that mediate the majority of fast synaptic inhibition in the brain. The K(+)/Cl(-) cotransporter KCC2 is the main mechanism by which neurons establish low intracellular Cl(-) levels, which is thought to enable GABAergic inhibitory control of neuronal activity. However, the widely used KCC2 inhibitor furosemide is nonselective with antiseizure efficacy in slices and in vivo, leading to a conflicting scheme of how KCC2 influences GABAergic control of neuronal synchronization. Here we used the selective KCC2 inhibitor VU0463271 [N-cyclopropyl-N-(4-methyl-2-thiazolyl)-2-[(6-phenyl-3-pyridazinyl)thio]acetamide] to investigate the influence of KCC2 function. Application of VU0463271 caused a reversible depolarizing shift in E(GABA) values and increased spiking of cultured hippocampal neurons. Application of VU0463271 to mouse hippocampal slices under low-Mg(2+) conditions induced unremitting recurrent epileptiform discharges. Finally, microinfusion of VU0463271 alone directly into the mouse dorsal hippocampus rapidly caused epileptiform discharges. Our findings indicated that KCC2 function was a critical inhibitory factor ex vivo and in vivo.

KEYWORDS:

GABAA; KCC2; VU0463271; chloride; seizures; slices

PMID:
26019342
PMCID:
PMC4444547
DOI:
10.1523/JNEUROSCI.5205-14.2015
[Indexed for MEDLINE]
Free PMC Article

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