Spontaneous epileptic seizures in transgenic rats harboring a human ADNFLE missense mutation in the β2-subunit of the nicotinic acetylcholine receptor

Shiba, Yuko; Mori, Fumiaki; Yamada, Jun; Migita, Keisuke; Nikaido, Yoshikazu; Wakabayashi, Keiji; Kaneko, Sunao; Okada, Motohiro; Hirose, Shinichi; Ueno, Shinji

doi:10.1016/j.neures.2015.06.003

Cited by 17 publications

(21 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cellular analysis in this mouse model is limited to the relatively crude synaptosome preparation, but does reveal increased sensitivity of acetylcholinergic-mediated release of dopamine (O'Neill et al, 2013). A transgenic rat with a gain-offunction mutation also displays infrequent spontaneous epileptic seizures that are described as being similar to paroxysmal arousals observed in human ADNFLE, providing another potential preclinical model (Shiba et al, 2015).…”

Section: Nicotinic Acetylcholine Receptors (Chrna4 Chrnb2 and Chmentioning

confidence: 99%

Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies

Oyrer¹,

Maljevic²,

Scheffer³

et al. 2017

Pharmacol Rev

225

190

View full text Add to dashboard Cite

Epilepsy is a common and serious neurologic disease with a strong genetic component. Genetic studies have identified an increasing collection of disease-causing genes. The impact of these genetic discoveries is wide reaching-from precise diagnosis and classification of syndromes to the discovery and validation of new drug targets and the development of disease-targeted therapeutic strategies. About 25% of genes identified in epilepsy encode ion channels. Much of our understanding of disease mechanisms comes from work focused on this class of protein. In this study, we review the genetic, molecular, and physiologic evidence supporting the pathogenic role of a number of different voltage- and ligand-activated ion channels in genetic epilepsy. We also review proposed disease mechanisms for each ion channel and highlight targeted therapeutic strategies.

show abstract

Section: Nicotinic Acetylcholine Receptors (Chrna4 Chrnb2 and Chmentioning

confidence: 99%

Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies

Oyrer¹,

Maljevic²,

Scheffer³

et al. 2017

Pharmacol Rev

225

190

View full text Add to dashboard Cite

show abstract

“…To explore the pathogenesis of ADSHE/SHE, several animal models have been generated (Klaassen et al, ; Shiba et al, ; Teper et al, ; Zhu et al, ). In other respects, although functional abnormality in thalamocortical transmission is known to contribute to cognitive impairment (Alelu‐Paz & Gimenez‐Amaya, ; Fukuyama, Hasegawa, & Okada, ; Fukuyama, Kato, Murata, Shiroyama, & Okada, ; Okada et al, ; Okada, Fukuyama, Kawano, Shiroyama, & Ueda, ; Okada, Fukuyama, Nakano, & Ueda, ; Okada, Fukuyama, Shiroyama, & Ueda, ; Schuetze et al, ; Vertes, Linley, & Hoover, ) and propagation of epileptic discharge (Bertram, ), more intrinsic functional changes specific to these models remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis and pathophysiology of autosomal dominant sleep‐related hypermotor epilepsy with S284L‐mutant α4 subunit of nicotinic ACh receptor

Fukuyama

Fukuzawa

Shiroyama

et al. 2020

British J Pharmacology

Self Cite

128

View full text Add to dashboard Cite

Background and Purpose: The mechanisms causing spontaneous epileptic seizures, including carbamazepine-resistant/zonisamide -sensitive seizures and comorbidity in autosomal dominant sleep-related hypermotor epilepsy (ADSHE) are unclear. This study investigated functional abnormalities in thalamocortical transmission in transgenic rats bearing rat S286L-mutant Chrna4 (S286L-TG) of α4 subunit of the nicotinic ACh receptor (nAChR) that corresponds to the human S284L-mutant CHRNA4.Experimental Approach: Effects of carbamazepine and zonisamide on epileptic discharges of S286L-TG rat were measured using telemetry electrocorticogram.Transmission abnormalities of L-glutamate and GABA in thalamocortical pathway of S286L-TG rats were investigated using multiprobe microdialysis and ultra-highperformance liquid-chromatography.Key Results: Epileptic discharges in S286L-TG rats were reduced by zonisamide but not by carbamazepine, similar to that of S284L-ADSHE patients. Carbamazepine unaffected functional abnormality in transmission of S286L-TG rats. However, zonisamide was able to compensate for the attenuated S286L-mutant nAChR induced GABA release in frontal-cortex, without affecting attenuated thalamocortical glutamatergic transmission. Excitatory effects of S286L-mutant nAChR on thalamocortical transmission were attenuated compared with those of wild-type nAChR. Loss-of-function of S286L-nAChR enhanced transmission in thalamocortical motor pathway by predominantly attenuating GABAergic transmission. However, it attenuated transmission in thalamocortical cognitive pathway by reducing inhibitory GABAergic and excitatory glutamatergic transmission. Conclusion and Implications:Our results suggest that functional abnormalities of S286L-nAChR are associated with intra-frontal and thalamocortical transmission, possibly contributing to the pathogenesis of ADSHE-seizure and comorbidity of S284L-ADSHE. Selective compensation of impaired GABAergic transmission by zonisamide (but not by carbamazepine) in frontal cortex may be involved, at least partially, in carbamazepine-resistant ADSHE-seizure of S284L-ADSHE patients. thalamic nucleus; SHE, sporadic form sleep-related hypermotor epilepsy; S286L-TG, transgenic rat bearing rat Chrna4 missense S286L mutation; ZNS, zonisamide.

show abstract

“…Some of the autosomal dominant NFLEs have been found to be caused by mutations of genes encoding the neuronal nicotinic acetylcholine receptor (AChR) subunits, resulting in increased AChR sensitivity. 75 , 76 Changes in prefrontal γ-aminobutyric acid release and other than AChR genes have recently been described. 77 …”

Section: The Pathophysiology Of Apsmentioning

confidence: 99%

Progress in elucidating the pathophysiological basis of nonrapid eye movement parasomnias: not yet informing therapeutic strategies

Horváth

Papp

Szücs

2016

NSS

View full text Add to dashboard Cite

Nonrapid eye movement (NREM) or arousal parasomnias are prevalent conditions in children and young adults, apparently provoked by any medical, physical, mental, or pharmacologic/toxic agent disturbing normal biorhythm and causing sleep fragmentation or abundant amount of slow wave sleep. The nadir and the ascending slope of the first sleep cycle of night sleep are the typical periods when NREM parasomnias, especially sleepwalking may occur on sleep-microstructural level; microarousals are the typical moments allowing NREM parasomnias. While sleep-disturbing factors have a clear precipitating effect, a genetic predisposition appears necessary in most cases. A candidate gene for sleepwalking has been identified on chromosome 20q12-q13.12 in one sleepwalking family. NREM parasomnias have a genetic and clinical link with nocturnal-frontal lobe epilepsies; possibly through an abnormality of the acetylcholine-related sleep-control system. The association of NREM parasomnias with the human leukocyte antigen system might be the sign of an autoimmune background to be further clarified. In the treatment of arousal parasomnias, the main tools are adequate sleep hygiene and the management of underlying conditions. Their pharmacotherapy has remained unresolved; the best options are clonazepam and some of the antidepressants, while a psychotherapy approach is also justified.

show abstract

Spontaneous epileptic seizures in transgenic rats harboring a human ADNFLE missense mutation in the β2-subunit of the nicotinic acetylcholine receptor

Cited by 17 publications

References 30 publications

Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies

Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies

Pathogenesis and pathophysiology of autosomal dominant sleep‐related hypermotor epilepsy with S284L‐mutant α4 subunit of nicotinic ACh receptor

Progress in elucidating the pathophysiological basis of nonrapid eye movement parasomnias: not yet informing therapeutic strategies

Contact Info

Product

Resources

About