Abstract
To study the pathomechanism and pathophysiology of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), this study determined functional abnormalities of glutamatergic transmission in the thalamocortical motor pathway, from the reticular thalamic nucleus (RTN), motor thalamic nuclei (MoTN) tosecondary motor cortex (M2C) associated with the S286L-mutant α4β2-nicotinic acetylcholine receptor (nAChR) and the connexin43 (Cx43) hemichannel of transgenic rats bearing the rat S286L-mutant Chrna4 gene (S286L-TG), which corresponds to the human S284L-mutant CHRNA4 gene using multiprobe microdialysis, primary cultured astrocytes and a Simple Western system. Expression of Cx43 in the M2C plasma membrane fraction of S286L-TG was upregulated compared with wild-type rats. Subchronic nicotine administration decreased Cx43 expression of wild-type, but did not affect that of S286L-TG; however, zonisamide (ZNS) decreased Cx43 in both wild-type and S286L-TG. Primary cultured astrocytes of wild-type were not affected by subchronic administration of nicotine but was decreased by ZNS. Upregulated Cx43 enhanced glutamatergic transmission during both resting and hyperexcitable stages in S286L-TG. Furthermore, activation of glutamatergic transmission associated with upregulated Cx43 reinforced the prolonged Cx43 hemichannel activation. Subchronic administration of therapeutic-relevant doses of ZNS compensated the upregulation of Cx43 and prolonged reinforced activation of Cx43 hemichannel induced by physiological hyperexcitability during the non-rapid eye movement phase of sleep. The present results support the primary pathomechanisms and secondary pathophysiology of ADSHE seizures of patients with S284L-mutation.
Highlights
Until recently, numerous gene mutations of ion channels, which regulate neuronal excitabilities in the central nervous system, have been identified in the various pedigrees of idiopathic epilepsy syndromes
The third was that the M2C itself cannot independently generate epileptic discharge, whereas the M2C can integrate external excitatory inputs from the thalamocortical motor pathway (MoTN-M2C pathway), resulting in the generation of epileptic discharges in the M2C [21]. These findings suggest the pathomechanisms of three major Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) seizures, ‘nocturnal paroxysmal arousals’, ‘nocturnal paroxysmal dystonia’ and ‘episodic nocturnal wandering’ [21,22]
Local administration of GAP19 into the M2C inhibited L-glutamate release induced by Amino-3-(3-hydroxy-5-methyl -isoxazol-4-yl)propanoic acid (AMPA)-evoke stimulation in the motor thalamic nuclei (MoTN) of S286L-TG without affecting that of wild-type. These results indicate that upregulated Cx43 in focus regions of S286L-TG is possibly induced by impaired inhibitory regulation of α4β2-nicotinic acetylcholine receptor (nAChR)
Summary
Numerous gene mutations of ion channels, which regulate neuronal excitabilities in the central nervous system, have been identified in the various pedigrees of idiopathic epilepsy syndromes. Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) [2] was first identified as distinct familial idiopathic epilepsy (previously ADNFLE: autosomal dominant nocturnal frontal lobe epilepsy) in 1994 [3]. ADSHE seizures are symptomatically comparable to those seen in frontal lobe epilepsy and occur predominantly during the non-rapid eye movement sleep phase [2,4,5,6]. These seizures are complex, stereotyped hyperkinetic seizures that consist of three types of motor seizures, ‘nocturnal paroxysmal arousals’, ‘nocturnal paroxysmal dystonia’ and ‘episodic nocturnal wandering’ [2,4,5,6]. Any observed clinical phenotypes have been considered to belong uniformly to ADSHE/SHE syndrome [2]
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