Upregulation of inward rectifier K+ (Kir2) channels in dentate gyrus granule cells in temporal lobe epilepsy

Young, Christina C. and Stegen, Michael and Bernard, René and Müller, Martin and Bischofberger, Josef and Veh, Rüdiger W. and Haas, Carola A. and Wolfart, Jakob. (2009) Upregulation of inward rectifier K+ (Kir2) channels in dentate gyrus granule cells in temporal lobe epilepsy. The journal of physiology : a publication of the Physiological Society, Vol. 587. pp. 4213-4233.

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Official URL: http://edoc.unibas.ch/dok/A6003880

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In humans, temporal lobe epilepsy (TLE) is often associated with Ammon's horn sclerosis (AHS) characterized by hippocampal cell death, gliosis and granule cell dispersion (GCD) in the dentate gyrus. Granule cells surviving TLE have been proposed to be hyperexcitable and to play an important role in seizure generation. However, it is unclear whether this applies to conditions of AHS. We studied granule cells using the intrahippocampal kainate injection mouse model of TLE, brain slice patch-clamp recordings, morphological reconstructions and immunocytochemistry. With progressing AHS and GCD, 'epileptic' granule cells of the injected hippocampus displayed a decreased input resistance, a decreased membrane time constant and an increased rheobase. The resting leak conductance was doubled in epileptic granule cells and roughly 70-80% of this difference were sensitive to K(+) replacement. Of the increased K(+) leak, about 50% were sensitive to 1 mm Ba(2+). Approximately 20-30% of the pathological leak was mediated by a bicuculline-sensitive GABA(A) conductance. Epileptic granule cells had strongly enlarged inwardly rectifying currents with a low micromolar Ba(2+) IC(50), reminiscent of classic inward rectifier K(+) channels (Irk/Kir2). Indeed, protein expression of Kir2 subunits (Kir2.1, Kir2.2, Kir2.3, Kir2.4) was upregulated in epileptic granule cells. Immunolabelling for two-pore weak inward rectifier K(+) channels (Twik1/K2P1.1, Twik2/K2P6.1) was also increased. We conclude that the excitability of granule cells in the sclerotic focus of TLE is reduced due to an increased resting conductance mainly due to upregulated K(+) channel expression. These results point to a local adaptive mechanism that could counterbalance hyperexcitability in epilepsy.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Physiology > Cellular Neurophysiology (Bischofberger)
UniBasel Contributors:Bischofberger, Josef
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:04 Jan 2013 08:38
Deposited On:04 Jan 2013 08:37

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