Deletion of the Na-K-2Cl cotransporter NKCC1 results in a more severe epileptic phenotype in the intrahippocampal kainate mouse model of temporal lobe epilepsy.

Abstract

Increased neuronal expression of the Na-K-2Cl cotransporter NKCC1 has been implicated in the generation of seizures and epilepsy. However, conclusions from studies on the NKCC1-specific inhibitor, bumetanide, are equivocal, which is a consequence of the multiple potential cellular targets and poor brain penetration of this drug. Here, we used Nkcc1 knockout (KO) and wildtype (WT) littermate control mice to study the ictogenic and epileptogenic effects of intrahippocampal injection of kainate. Kainate (0.23 μg in 50 nl) induced limbic status epilepticus (SE) in both KO and WT mice with similar incidence, latency to SE onset, and SE duration, but the number of intermittent generalized convulsive seizures during SE was significantly higher in Nkcc1 KO mice, indicating increased SE severity. Following SE, spontaneous recurrent seizures (SRS) were recorded by continuous (24/7) video/EEG monitoring at 0-1, 4-5, and 12-13 weeks after kainate, using depth electrodes in the ipsilateral hippocampus. Latency to onset of electrographic SRS and the incidence of electrographic SRS were similar in WT and KO mice. However, the frequency of electrographic seizures was lower whereas the frequency of electroclinical seizures was higher in Nkcc1 KO mice, indicating a facilitated progression from electrographic to electroclinical seizures during chronic epilepsy, and a more severe epileptic phenotype, in the absence of NKCC1. The present findings suggest that NKCC1 is dispensable for the induction, progression and manifestation of epilepsy, and they do not support the widely held notion that inhibition of NKCC1 in the brain is a useful strategy for preventing or modifying epilepsy.

• Authors: Philip Hampel, Marie Johne, Björn Gailus, Alexandra Vogel, Alina Schidlitzki, Birthe Gericke, Kathrin Töllner, Wiebke Theilmann, Christopher Käufer, Kerstin Römermann, Kai Kaila, Wolfgang Löscher
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 152 Pg. 105297 (05 2021) ISSN: 1095-953X [Electronic] United States
• PMID: 33581254 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Convulsants
• Slc12a2 protein, mouse
• Solute Carrier Family 12, Member 2
• Kainic Acid

Topics

• Animals
• Convulsants (toxicity)
• Disease Models, Animal
• Epilepsy, Temporal Lobe (chemically induced, metabolism)
• Female
• Kainic Acid (toxicity)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phenotype
• Solute Carrier Family 12, Member 2 (metabolism)