Selective Inhibition of KCC2 Leads to Hyperexcitability and Epileptiform Discharges in Hippocampal Slices and in Vivo

Sudhir Sivakumaran, Ross A Cardarelli, Jamie Maguire, Matt R Kelley, Liliya Silayeva, Danielle H Morrow, Jayanta Mukherjee, Yvonne E Moore, Robert J Mather, Mark E Duggan, Nicholas J Brandon, John Dunlop, etc.

J Neurosci. 2015 May 27;35(21):8291-6.

PMID: 26019342

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1391737011	VU0463271		1391737-01-1	Price