Abstract
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 α4β2-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.
Highlights
Numerous mutations of genes encoding various ion channels, which regulate transmission in the central nervous system, were identified in the various idiopathic epilepsy pedigrees
Autosomal dominant sleep-related hypermotor epilepsy (ADSHE), the first identified as a distinct familial idiopathic epilepsy in 1994 [2,3], was reported as a channelopathy caused by a mutation in the CHRNA4 gene, which encodes α4 subunit of nicotinic acetylcholine receptor
The first-choice anticonvulsant against ADSHE, carbamazepine (CBZ), improves prognosis, and approximately 60% of ADSHE patients remission, including ADSHE patients with S280F and insL mutations of CHRNA4 [6,7,8], whereas ADSHE patients with S284L-mutation of CHRNA4 are usually resistant to CBZ, but improved by other anticonvulsants such as zonisamide (ZNS) [4,9,10,11,12]
Summary
Numerous mutations of genes encoding various ion channels, which regulate transmission in the central nervous system, were identified in the various idiopathic epilepsy pedigrees. Autosomal dominant sleep-related hypermotor epilepsy (ADSHE), the first identified as a distinct familial idiopathic epilepsy (previously, ADNFLE: autosomal dominant nocturnal frontal lobe epilepsy) in 1994 [2,3], was reported as a channelopathy caused by a mutation in the CHRNA4 gene, which encodes α4 subunit of nicotinic acetylcholine receptor (nAChR). Various mutations in several genes such as CHRNA2, CHRNA4, CHRNB2, CHR, KCNT1, and DEPDC5 have been identified in various pedigrees of ADSHE [3,4,5]. ADSHE seizures are symptomatically comparable to those seen in frontal lobe epilepsy and usually occur during the non-rapid eye movement sleep phase [3,4,5,6]. ADSHE with insL and S284L mutations comorbid with cognitive dysfunction, including schizophrenia-like psychosis, autism, and intellectual disability [10,11,12,15,18,19,20]
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