Upregulated Connexin 43 Induced by Loss-of-Functional S284L-Mutant α4 Subunit of Nicotinic ACh Receptor Contributes to Pathomechanisms of Autosomal Dominant Sleep-Related Hypermotor Epilepsy

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.

A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43

“…Indeed, the deficit/disruption of MDTN exhibited deficits in the regulation of learning, memory, emotion, and perceptual integration [ 97 , 98 , 99 , 100 , 101 ]. Contrary, the tonic activation of the thalamocortical glutamatergic pathway in experimental animal models of schizophrenia, attention-deficit hyperactivity disorder, and autism has been observed [ 76 , 77 , 84 , 85 , 94 , 102 , 103 , 104 , 105 , 106 , 107 ].…”

“…Research suggested that the upregulation of Cx43 in astrocytes exacerbated epileptic seizures in patients with temporal lobe epilepsy [ 143 ]. Preclinically, the upregulation of Cx43 in the focus region and focus generating neural circuits of a genetic sleep-related hypermotor epilepsy model, which included carbamazepine-resistant/zonisamide-sensitive epileptic seizures, were also observed [ 105 , 106 ]. Notably, both inputs of physiological and pathological neuronal excitability in the Cx43 upregulation regions provided the generation of epileptic discharges and accelerated the propagation of epileptic hyperexcitability [ 103 , 104 , 105 , 106 , 108 ].…”

“…Preclinically, the upregulation of Cx43 in the focus region and focus generating neural circuits of a genetic sleep-related hypermotor epilepsy model, which included carbamazepine-resistant/zonisamide-sensitive epileptic seizures, were also observed [ 105 , 106 ]. Notably, both inputs of physiological and pathological neuronal excitability in the Cx43 upregulation regions provided the generation of epileptic discharges and accelerated the propagation of epileptic hyperexcitability [ 103 , 104 , 105 , 106 , 108 ]. Indeed, zonisamide and lacosamide, which clinically suppressed carbamazepine-resistant epileptic seizure of sleep-related hypermotor epilepsy, reduced Cx43 expression and its function, respectively [ 103 , 105 , 106 ], whereas the anticonvulsive target of carbamazepine in astrocytes was not Cx43 [ 103 , 146 ].…”

“…Carbenoxolone, a Cx gap-junction/hemichannel inhibitor [ 103 , 105 , 106 ], ameliorated pulmonary inflammation in asthma animal models via the possible reduction in interleukin-4 and -5 production and decreasing the infiltration of inflammatory cells in perivascular regions ( Figure 3 ) [ 167 ]. In addition, carbenoxolone also decreased the differentiation of Th17 cells by a reduction in interleukin-23 production in antigen presenting cells [ 168 ].…”

Interaction between Mesocortical and Mesothalamic Catecholaminergic Transmissions Associated with NMDA Receptor in the Locus Coeruleus

“…The major thalamocortical glutamatergic pathways [32] composed of projection form the mediodorsal thalamic nucleus (MDTN) to the medial prefrontal cortex, insula, and orbitofrontal cortex (OFC) [26,27,30,31,[33][34][35][36][37][38][39]. These thalamocortical glutamatergic pathways contribute to the constitution of cognition, and to stability and flexibility against environmental changes [26][27][28][29][30][31]33,34,40,41]. In particular, mesothalamic noradrenergic transmission plays important roles in the appropriate response of thalamocortical glutamatergic transmission to various inputs [36].…”