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3 Publications visible to you, out of a total of 3
Persistent Kv7.2/7.3 downregulation in the rat pilocarpine model of mesial temporal lobe epilepsy.

Abstract (Expand)

Mutations within the Kv7.2 and Kv7.3 genes are well described causes for genetic childhood epilepsies. Knowledge on these channels in acquired focal epilepsy, especially in mesial temporal lobe epilepsy … (mTLE), however, is scarce. Here, we used the rat pilocarpine model of drug-resistant mTLE to elucidate both expression and function by quantitative polymerase-chain reaction, immunohistochemistry, and electrophysiology, respectively. We found transcriptional downregulation of Kv7.2 and Kv7.3 as well as reduced Kv7.2 expression in epileptic CA1. Consequences were altered synaptic transmission, hyperexcitability which consisted of epileptiform afterpotentials, and increased susceptibility to acute GABAergic disinhibition. Importantly, blocking Kv7 channels with XE991 increased hyperexcitability in control tissue, but not in chronically epileptic tissue suggesting that the Kv7 deficit had precluded XE991 effects in this tissue. Conversely, XE991 resulted in comparable reduction of the paired-pulse ratio in both experimental groups implying preserved presynaptic Kv7.2 function of Schaffer collateral terminals. Consistent with Kv7.2/7.3 downregulation, the Kv7.3 channel opener beta-hydroxybutyrate failed to mitigate hyperexcitability. Our findings demonstrate that compromised Kv7 function is not only relevant in genetic epilepsy, but also in acquired focal epilepsy. Moreover, they help explain reduced anti-seizure efficacy of Kv7 channel openers in drug-resistant epilepsy.

Authors: S. Muller, M. Kartheus, E. Hendinger, D. C. Hubner, E. Schnell, S. Rackow, A. Bertsche, R. Kohling, T. Kirschstein

Date Published: 23rd Feb 2024

Publication Type: Journal

K(v)7 and K(ir)6 Channels Shape the Slow AHP in Mouse Dentate Gyrus Granule Cells and Control Burst-like Firing Behavior.

Abstract (Expand)

The slow afterhyperpolarizing potential (sAHP) can silence a neuron for hundreds of milliseconds. Thereby, the sAHP determines the discharge behavior of many types of neurons. In dentate granule cells … (DGCs), serving as a filter into the hippocampal network, mostly tonic or adapting discharge properties have been described. As under standard whole-cell recording conditions the sAHP is inhibited, we reevaluated the intrinsic functional phenotype of DGCs and the conductances underlying the sAHP, using gramicidine-perforated patch-clamp technique. We found that in 97/113 (86%) of the DGCs, a burst of action potentials (APs) to excitation ended by a large sAHP, despite continued depolarization. This result suggests that burst-like firing is the default functional phenotype of DGCs and that sAHPs are important for it. Indeed, burst-like firing DGCs showed a significantly higher sAHP-current (I(sAHP)) amplitude compared to spike-frequency adapting cells (16/113 = 14%). The I(sAHP) was mediated by K(v)7 and K(ir)6 channels by pharmacological inhibition using XE991 and tolbutamide, although heterogeneously among DGCs. The percent inhibition of I(sAHP) by these compounds also correlated with the AP number and AP burst length. Application of 100 microM nickel after XE991 and tolbutamide detected a third conductance contributing to burst-like firing and the sAHP, most likely mediated by T-type calcium channels. Lastly, medial perforant path-dentate gyrus long-term potentiation was amplified by XE991 and tolbutamide. In conclusion, the sAHP shapes intrinsic burst-like firing which, under physiological circumstances, could be controlled via cholinergic afferents and ATP metabolism.

Authors: D. Laker, F. Tolle, M. Stegen, M. Heerdegen, R. Kohling, T. Kirschstein, J. Wolfart

Date Published: 15th Jul 2021

Publication Type: Journal

Oral administration of the casein kinase 2 inhibitor TBB leads to persistent K(Ca)2.2 channel up-regulation in the epileptic CA1 area and cortex, but lacks anti-seizure efficacy in the pilocarpine epilepsy model.

Abstract (Expand)

Temporal lobe epilepsy (TLE) is the most common epileptic syndrome in adults and often presents with seizures that prove intractable with currently available anticonvulsants. Thus, there is still a … need for new anti-seizure drugs in this condition. Recently, we found that the casein kinase 2 inhibitor 4,5,6,7-tetrabromotriazole (TBB) prevented the emergence of spontaneous epileptic discharges in an acute in vitro epilepsy model. This prompted us to study the anti-seizure effects of TBB in the pilocarpine model of chronic epilepsy in vivo. To this end, we performed long-term video-EEG monitoring lasting 78-167 days of nine chronically epileptic rats and obtained a baseline seizure rate of 3.3 +/- 1.3 per day (baseline of 27-80 days). We found a significant age effect with more pronounced seizure rates in older animals as compared to younger ones. However, the seizure rate increased to 6.3 +/- 2.2 per day during the oral TBB administration (treatment period of 21-50 days), and following discontinuation of TBB, this rate remained stable with 5.2 +/- 1.4 seizures per day (follow-up of 30-55 days). After completing the video-EEG during the follow-up the hippocampal tissue was prepared and studied for the expression of the Ca(2+)-activated K(+) channel K(Ca)2.2. We found a significant up-regulation of K(Ca)2.2 in the epileptic CA1 region and in the neocortex, but in no other hippocampal subfield. Hence, our findings indicate that oral administration of TBB leads to persistent up-regulation of K(Ca)2.2 in the epileptic CA1 subfield and in the neocortex, but lacks anti-seizure efficacy in the pilocarpine epilepsy model.

Authors: R. Bajorat, K. Porath, J. Kuhn, E. Gossla, D. Goerss, T. Sellmann, R. Kohling, T. Kirschstein

Date Published: 17th Sep 2018

Publication Type: Journal

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