Upregulated and Hyperactivated Thalamic Connexin 43 Plays Important Roles in Pathomechanisms of Cognitive Impairment and Seizure of Autosomal Dominant Sleep-Related Hypermotor Epilepsy with S284L-Mutant α4 Subunit of Nicotinic ACh Receptor
Upregulated and Hyperactivated Thalamic Connexin 43 Plays Important Roles in Pathomechanisms of Cognitive Impairment and Seizure of Autosomal Dominant Sleep-Related Hypermotor Epilepsy with S284L-Mutant α4 Subunit of Nicotinic ACh Receptor
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DOI：
10.3390/ph13050099
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发表时间：
2020-05-01
期刊：
影响因子：
4.6
通讯作者：
Okada, Motohiro
中科院分区：
文献类型：
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作者：
Fukuyama, Kouji;Fukuzawa, Masashi;Okada, Motohiro
为了解常染色体显性显性睡眠相关性多运动性癫痫（ADSHE）的病理机制和病理生理，我们研究了与s286l突变体α 4 β 2-烟碱受体（nAChR）相关的丘脑皮质通路中从丘脑网状核（RTN）、丘脑中背核（MDTN）到眶额皮质（OFC）谷氨酸能传递的功能异常。和connexin43 （Cx43）半通道，转基因大鼠携带大鼠s286l突变体Chrna4基因（S286L-TG），与人类s284l突变体Chrna4基因相对应。与野生型相比，S286L-TG丘脑质膜部分Cx43表达上调。亚慢性治疗相关剂量的唑尼沙胺（ZNS）和卡马西平（CBZ）分别降低且不影响S286L-TG的Cx43表达。上调的Cx43增强了S286L-TG在静息期和高兴奋期的谷氨酸能传递。此外，gaba能传递RTN-MDTN通路的激活通过上调/激活的Cx43反过来增强而非抑制MDTN中l-谷氨酸的释放。局部给予治疗相关浓度的ZNS和CBZ分别急性抑制丘脑皮质通路中的谷氨酸能传递，但不影响谷氨酸传递。这些结果提示了s284l突变患者ADSHE发作及其认知缺陷合并症的病理机制，以及cbz耐药/ zns敏感ADSHE发作的病理生理机制。
To understand the pathomechanism and pathophysiology of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), we studied functional abnormalities of glutamatergic transmission in thalamocortical pathway from reticular thalamic nucleus (RTN), mediodorsal thalamic nucleus (MDTN) to orbitofrontal cortex (OFC) associated with S286L-mutant alpha 4 beta 2-nicotinic acetylcholine receptor (nAChR), and connexin43 (Cx43) hemichannel of transgenic rats bearing rat S286L-mutant Chrna4 gene (S286L-TG), corresponding to the human S284L-mutant CHRNA4 gene using simple Western analysis and multiprobe microdialysis. Cx43 expression in the thalamic plasma membrane fraction of S286L-TG was upregulated compared with that of wild-type. Subchronic administrations of therapeutic-relevant doses of zonisamide (ZNS) and carbamazepine (CBZ) decreased and did not affect Cx43 expression of S286L-TG, respectively. Upregulated Cx43 enhanced glutamatergic transmission during both resting and hyperexcitable stages in S286L-TG. Furthermore, activation of GABAergic transmission RTN-MDTN pathway conversely enhanced, but not inhibited, l-glutamate release in the MDTN via upregulated/activated Cx43. Local administration of therapeutic-relevant concentration of ZNS and CBZ acutely supressed and did not affect glutamatergic transmission in the thalamocortical pathway, respectively. These results suggest that pathomechanisms of ADSHE seizure and its cognitive deficit comorbidity, as well as pathophysiology of CBZ-resistant/ZNS-sensitive ADSHE seizures of patients with S284L-mutation.