Selective inhibition of KCC2 leads to hyperexcitability and epileptiform discharges in hippocampal slices and in vivo
| Autor: | Tarek Z. Deeb, Mark E. Duggan, Jamie Maguire, Nicholas J. Brandon, Stephen J. Moss, Liliya Silayeva, Matt R. Kelley, John Dunlop, Sudhir Sivakumaran, Stephen Zicha, Robert J. Mather, Ross A. Cardarelli, Yvonne E. Moore, Jayanta Mukherjee, Danielle H. Morrow |
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| Rok vydání: | 2015 |
| Předmět: |
Hippocampus
Neurotransmission Hippocampal formation Biology Inhibitory postsynaptic potential Synaptic Transmission Membrane Potentials Rats Sprague-Dawley 03 medical and health sciences Mice 0302 clinical medicine Organ Culture Techniques Sodium Potassium Chloride Symporter Inhibitors Premovement neuronal activity Animals Humans Cells Cultured 030304 developmental biology 0303 health sciences Symporters GABAA receptor General Neuroscience Depolarization 3. Good health Rats Mice Inbred C57BL HEK293 Cells nervous system Animals Newborn GABAergic Brief Communications Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience. 35(21) |
| ISSN: | 1529-2401 |
| Popis: | GABAAreceptors 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 andin 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 inEGABAvalues and increased spiking of cultured hippocampal neurons. Application of VU0463271 to mouse hippocampal slices under low-Mg2+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 factorex vivoandin vivo. |
| Databáze: | OpenAIRE |
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