The role of voltage-gated chloride channels in the epileptogenesis of temporal lobe epilepsy

Abstract

Background: Temporal lobe epilepsy (TLE) is the most common intractable epilepsy in adults, and elucidation of the underlying pathological mechanisms is needed. Voltage-gated chloride channels (ClC) play diverse physiological roles in neurons. However, less is known regarding their functions in the epilepogenesis of TLE. Methods: ClC-mediated current and the spontaneous inhibitory synaptic currents (sIPSC) in hippocampal neurons of epileptic lesions were investigated by electrophysiological recording. The EEG data were analyzed by Z-scored wavelet and Fourier transformations. The expression of ClC-3, a member of ClC gene family, was detected by immunostaining and western blot. Findings: ClC-mediated current was increased in the hippocampal neurons of chronic TLE mice. Application of chloride channel blockers, NPPB (5-Nitro-2-[3-phenylpropylamino] benzoic acid) and DIDS (4,4'-Diisothiocyanato-2,2'-stilbenedisulfonic acid disodium salt) reduced ClC-mediated current and increased inhibitory synaptic transmission in TLE mice. NPPB and DIDS reduced the seizure frequency and the average absolute power of ictal high-frequency oscillations (HFOs, 80-500 Hz) in TLE mice. In addition, both drugs induced outwardly rectified currents, which might be tonic inhibitory currents in the hippocampal neurons of TLE patients. Furthermore, the expression of ClC-3 was increased in the hippocampus of TLE mice and patients and positively correlated with both the absolute power and number of ictal HFOs per seizure in the sclerotic hippocampus. Interpretation: These data suggest that ClC participate in the epilepogenetic process of TLE and the inhibition of ClC may have anti-epileptic effect.

Association Between COVID-19 and Neurological Diseases: Evidence from Large-Scale Mendelian Randomization Analysis and Single-Cell RNA Sequencing Analysis

“…TTYH2 not only acts as a receptor for the SARS-CoV-2 but also as a calciumactivated chloride channel (CaCCs). Voltage-gated chloride channels (ClC) participate in the epileptogenesis process of epilepsy, and the inhibition of ClC may have anti-epileptic effect [53,54]. Thus, the unbalanced expression levels of TTYH2 were one of the reasons for concomitant epilepsy in patients with COVID-19.…”

Microscale Neuronal Activity Collectively Drives Chaotic and Inflexible Dynamics at the Macroscale in Seizures

“…Therefore, dense connectivity may instead be explained by the formation of new effective connections between neurons – these could arise through a diversity of mechanisms, such as volume transmitted GABA waves diffusing extracellularly ( Magloire et al, 2022 ), or glia-glia coupling via gap junctions which can synchronise non-coupled neurons ( Diaz Verdugo et al, 2019 ). However, a diversity of other microscale parameters not explored here have been shown to drive epileptic seizures – including intracellular Cl- ( Huberfeld et al, 2007 ; Magloire et al, 2019 ; Shen et al, 2021 ; Staley, 2006 ), extracellular K+ ( Florence et al, 2009 ; Uva et al, 2017 ; Ying et al, 2015 ), pro-ictal inhibition ( Chang et al, 2018 ; Miri et al, 2018 ), distinct neuronal cell type dynamics ( Khoshkhoo et al, 2017 ; Makinson et al, 2017 ), and cell death ( Dingledine et al, 2014 ; Sloviter, 1987 ). Future work should use more specific parameterisations, to disentangle the differential role of each of these microscale parameters in driving excessive network connectivity during seizures.…”

Clinical Neurophysiology of Epileptogenic Networks

“…Epileptogenic depolarizing currents can emerge from abnormal or excessive ionic Na + [91] and Ca ++ [92] channel-conductances or excessive excitatory (Glutamate) and neuromodulatory (Acetylcholine, Noradrenaline, Dopamine, Serotonin, etc) neurotransmitter release and receptor function [87][88][89]. Epileptogenic afterhyperpolarizing currents can emerge from abnormal, insufficient or excessive ionic Cl À [93] and K + [94][95][96] channel-conductances or abnormal, insufficient or excessive inhibitory (GABA) neurotransmitter release and receptor function [85,86]. Multiple combinations of the above epileptogenic mechanisms are plausible.…”

“…These ultimately determine the intrinsic excitability and oscillatory dynamics of the individual neuron and its interactions with other structurally/functionally interconnected neurons. The membrane excitability characteristics and shortening of time integration constant (via a "push-and-pull" mechanism) of synchronized, coincidental or critically interacting excitatory (EPSP) and inhibitory (IPSP) postsynaptic potentials can increase or decrease the excitability of the entire network (Figure 26) [79,[85][86][87][88][89][90][91][92][93][94][95][96][97].…”