Seizures and Epilepsies due to Channelopathies and Neurotransmitter Receptor Dysfunction: A Parallel between Genetic and Immune Aspects

Lascano, Agustina Maria; Korff, Christian; Picard, Fabienne

doi:10.1159/000447707

Cited by 17 publications

(7 citation statements)

References 118 publications

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“…Various channelopathies, including mutated or misregulated K + channels, have been suggested to underlie certain forms of genetic epilepsies (D’Adamo et al, 2013; Lascano et al, 2016). Indeed, mutations in K V 4 α-subunits are present in some patients suffering from pharmacoresistant temporal lobe epilepsy (Singh et al, 2006; D’Adamo et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Role of KCC2-dependent potassium efflux in 4-Aminopyridine-induced Epileptiform synchronization

González

Shiri

Krishnan

et al. 2018

Neurobiology of Disease

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A balance between excitation and inhibition is necessary to maintain stable brain network dynamics. Traditionally, seizure activity is believed to arise from the breakdown of this delicate balance in favor of excitation with loss of inhibition. Surprisingly, recent experimental evidence suggests that this conventional view may be limited, and that inhibition plays a prominent role in the development of epileptiform synchronization. Here, we explored the role of the KCC2 co-transporter in the onset of inhibitory network-induced seizures. Our experiments in acute mouse brain slices, of either sex, revealed that optogenetic stimulation of either parvalbumin- or somatostatin-expressing interneurons induced ictal discharges in rodent entorhinal cortex during 4-aminopyridine application. These data point to a proconvulsive role of GABA receptor signaling that is independent of the inhibitory input location (i.e., dendritic vs. somatic). We developed a biophysically realistic network model implementing dynamics of ion concentrations to explore the mechanisms leading to inhibitory network-induced seizures. In agreement with experimental results, we found that stimulation of the inhibitory interneurons induced seizure-like activity in a network with reduced potassium A-current. Our model predicts that interneuron stimulation triggered an increase of interneuron firing, which was accompanied by an increase in the intracellular chloride concentration and a subsequent KCC2-dependent gradual accumulation of the extracellular potassium promoting epileptiform ictal activity. When the KCC2 activity was reduced, stimulation of the interneurons was no longer able to induce ictal events. Overall, our study provides evidence for a proconvulsive role of GABA receptor signaling that depends on the involvement of the KCC2 co-transporter.

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Section: Discussionmentioning

confidence: 99%

Role of KCC2-dependent potassium efflux in 4-Aminopyridine-induced Epileptiform synchronization

González

Shiri

Krishnan

et al. 2018

Neurobiology of Disease

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“…14 SCA type 6 is caused by a CAG repeat in a calcium channel CACNA1A heavily expressed in the cerebellum. 92 Other observations that might also point to a trinucleotide repeat expansion or channelopathy underlying FCMTE include in Asian FCMTE pedigrees, progressively earlier onset of the disease with increasing severity in successive generations [19][20][21] ; presence of migraine [15][16][17][18] analogues to hemiplegic migraine with mutations in calcium channels 93 ; and the recognition that certain epilepsy syndromes are channelopathies. 45,94 Recently, an autosomal recessive form of FCMTE has been recognized with a single base pair deletion in CNTN2, crucial for the stability of potassium channels.…”

Section: Possible Candidate Genesmentioning

confidence: 99%

Familial Cortical Myoclonic Tremor and Epilepsy, an Enigmatic Disorder: From Phenotypes to Pathophysiology and Genetics. A Systematic Review

Ende

Sharifi

Salm

et al. 2018

Tremor and Other Hyperkinetic Movements

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Background: Autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE) is characterized by distal tremulous myoclonus, generalized seizures, and signs of cortical reflex myoclonus. FCMTE has been described in over 100 pedigrees worldwide, under several different names and acronyms. Pathological changes have been located in the cerebellum. This systematic review discusses the clinical spectrum, treatment, pathophysiology, and genetic findings.Methods: We carried out a PubMed search, using a combination of the following search terms: cortical tremor, myoclonus, epilepsy, benign course, adult onset, familial, and autosomal dominant; this resulted in a total of 77 studies (761 patients; 126 pedigrees) fulfilling the inclusion and exclusion criteria.Results: Phenotypic differences across pedigrees exist, possibly related to underlying genetic differences. A ''benign'' phenotype has been described in several Japanese families and pedigrees linked to 8q (FCMTE1). French patients (5p linkage; FCMTE3) exhibit more severe progression, and in Japanese/Chinese pedigrees (with unknown linkage) anticipation has been suggested. Preferred treatment is with valproate (mind teratogenicity), levetiracetam, and/or clonazepam.Several genes have been identified, which differ in potential pathogenicity.Discussion: Based on the core features (above), the syndrome can be considered a distinct clinical entity. Clinical features may also include proximal myoclonus and mild progression with aging. Valproate or levetiracetam, with or without clonazepam, reduces symptoms. FCMTE is a heterogeneous disorder, and likely to include a variety of different conditions with mutations of different genes. Distinct phenotypic traits might reflect different genetic mutations. Genes involved in Purkinje cell outgrowth or those encoding for ion channels or neurotransmitters seem good candidate genes.

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“…groups. Imbalance of excitatory and inhibitory neurotransmitters may lead to epileptic seizures ( Lascano et al, 2016 ). Expressional alterations of receptors and ion channels activated by neurotransmitters can lead to pathogenesis of epilepsy ( Akyuz et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Hippocampus RNA Sequencing of Pentylenetetrazole-Kindled Rats and Upon Treatment of Novel Chemical Q808

Wang

Zhang

et al. 2022

Front. Pharmacol.

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The expression of genes altered in epilepsy remains incomplete, particularly in the hippocampus, which exhibits exquisite vulnerability to epilepsy. Q808 is an innovation chemical compound that has potent anti-convulsant effect. Exploring its mechanism can not only explore the pathogenesis of epilepsy but also provide a theoretical basis for its clinical application. The present study aimed to use RNA sequencing (RNA-seq) to reveal the gene transcriptomic profile of chronic pentylenetetrazole (PTZ)-kindled seizure rats and the difference of the PTZ model rat before and after treatment with Q808. Quantitative real-time PCR (qRT-PCR) was performed to validate the RNA-seq results. The protein level was estimated with Western blot. Hippocampal transcriptomic analysis showed that 289 differentially expressed genes (DEGs) were confirmed in the PTZ-kindled seizure group compared with the vehicle control. Gene cluster analysis identified most of the DEGs linked to neuronal apoptosis, neurogenesis, neuronal projections, and neurotransmitter regulation. After analysis across the three groups, 23 hub genes and 21 pathways were identified, and qRT-PCR analysis confirmed that most of the mRNA levels of hub genes were consistent with the RNA-seq results. Q808 treatment increased the level of ACE, a GABA-related protein. Our analysis showed the comprehensive compendium of genes and pathways differentially expressed for PTZ-kindled seizure rats and upon Q808 treatment in PTZ-kindled seizure, which may provide a theoretical basis to explore the mechanism and unique efficacy of Q808 and the pathophysiology of epilepsy in the future.

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Seizures and Epilepsies due to Channelopathies and Neurotransmitter Receptor Dysfunction: A Parallel between Genetic and Immune Aspects

Cited by 17 publications

References 118 publications

Role of KCC2-dependent potassium efflux in 4-Aminopyridine-induced Epileptiform synchronization

Role of KCC2-dependent potassium efflux in 4-Aminopyridine-induced Epileptiform synchronization

Familial Cortical Myoclonic Tremor and Epilepsy, an Enigmatic Disorder: From Phenotypes to Pathophysiology and Genetics. A Systematic Review

Hippocampus RNA Sequencing of Pentylenetetrazole-Kindled Rats and Upon Treatment of Novel Chemical Q808

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