Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu, Mie 514-8507, Japan.
Department of Biology, Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki. 036-8560, Japan.
Biomed Pharmacother. 2020 Jun;126:110070. doi: 10.1016/j.biopha.2020.110070. Epub 2020 Mar 10.
To study the pathomechanism and pathophysiology of nocturnal paroxysmal dystonia of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), this study determined functional abnormalities in thalamic hyperdirect pathway from reticular thalamic nucleus (RTN), motor thalamic nuclei (MoTN), subthalamic nucleus (STN) to substantia nigra pars reticulata (SNr) of transgenic rats (S286L-TG) bearing S286 L missense mutation of rat Chrna4 gene, which corresponds to the S284 L mutation in the human CHRNA4 gene. The activation of α4β2-nAChR in the RTN increased GABA release in MoTN resulting in reduced glutamatergic transmission in thalamic hyperdirect pathway of wild-type. Contrary to wild-type, activation of S286L-mutant α4β2-nAChR (loss-of-function) in the RTN relatively enhanced glutamatergic transmission in thalamic hyperdirect pathway of S286L-TG via impaired GABAergic inhibition in intra-thalamic (RTN-MoTN) pathway. These functional abnormalities in glutamatergic transmission in hyperdirect pathway contribute to the pathomechanism of electrophysiologically negative nocturnal paroxysmal dystonia of S286L-TG. Therapeutic-relevant concentration of zonisamide (ZNS) inhibited the glutamatergic transmission in the hyperdirect pathway via activation of group II metabotropic glutamate receptor (II-mGluR) in MoTN and STN. The present results suggest that S286L-mutant α4β2-nAChR induces GABAergic disinhibition in intra-thalamic (RTN-MoTN) pathway and hyperactivation of glutamatergic transmission in thalamic hyperdirect pathway (MoTN-STN-SNr), possibly contributing to the pathomechanism of nocturnal paroxysmal dystonia of ADSHE patients with S284L mutant CHRNA4. Inhibition of glutamatergic transmission in thalamic hyperdirect pathway induced by ZNS via activation of II-mGluR may be involved, at least partially, in ZNS-sensitive nocturnal paroxysmal dystonia of ADSHE patients with S284L mutation.
为了研究常染色体显性遗传性睡眠相关运动过度性癫痫（ADSHE）夜间阵发性舞蹈徐动症的发病机制和病理生理学，本研究确定了携带 S286L 错义突变的大鼠（S286L-TG）丘脑超直接通路（来自网状丘脑核（RTN）、运动丘脑核（MoTN）、丘脑下核（STN）至黑质网状部（SNr））中的功能异常，该突变对应于人类 CHRNA4 基因中的 S284L 突变。RTN 中 α4β2-nAChR 的激活增加了 MoTN 中的 GABA 释放，导致野生型丘脑超直接通路中的谷氨酸能传递减少。与野生型相反，RTN 中 S286L 突变型 α4β2-nAChR（功能丧失）的激活通过损伤丘脑内（RTN-MoTN）通路中的 GABA 能抑制，相对增强了 S286L-TG 中丘脑超直接通路中的谷氨酸能传递。超直接通路中谷氨酸能传递的这些功能异常导致 S286L-TG 电生理阴性夜间阵发性舞蹈徐动症的发病机制。佐米曲普坦（ZNS）的治疗相关浓度通过激活 MoTN 和 STN 中的 II 型代谢型谷氨酸受体（II-mGluR）抑制超直接通路中的谷氨酸能传递。本研究结果表明，S286L 突变型 α4β2-nAChR 诱导丘脑内（RTN-MoTN）通路中的 GABA 能去抑制和丘脑超直接通路（MoTN-STN-SNr）中谷氨酸能传递的超激活，可能导致 S284L 突变 CHRNA4 患者 ADSHE 夜间阵发性舞蹈徐动症的发病机制。ZNS 通过激活 II-mGluR 抑制丘脑超直接通路中的谷氨酸能传递可能至少部分参与了 S284L 突变的 ADSHE 患者中 ZNS 敏感的夜间阵发性舞蹈徐动症。
