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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 ?4 Subunit of Nicotinic ACh Receptor.

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 ?4?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.

SUBMITTER: Fukuyama K

PROVIDER: S-EPMC7280967 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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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.

Fukuyama Kouji K Fukuzawa Masashi M Okada Motohiro M

Pharmaceuticals (Basel, Switzerland) 20200518 5

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 <i>Chrna4</i> gene (S286L-TG), ...[more]

PMID: 32443400

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Project description:Background and purposeThe mechanisms causing spontaneous epileptic seizures, including carbamazepine-resistant/zonisamide -sensitive seizures and comorbidity in autosomal dominant sleep-related hypermotor epilepsy (ADSHE) are unclear. This study investigated functional abnormalities in thalamocortical transmission in transgenic rats bearing rat S286L-mutant Chrna4 (S286L-TG) of α4 subunit of the nicotinic ACh receptor (nAChR) that corresponds to the human S284L-mutant CHRNA4.Experimental approachEffects of carbamazepine and zonisamide on epileptic discharges of S286L-TG rat were measured using telemetry electrocorticogram. Transmission abnormalities of L-glutamate and GABA in thalamocortical pathway of S286L-TG rats were investigated using multiprobe microdialysis and ultra-high-performance liquid-chromatography.Key resultsEpileptic discharges in S286L-TG rats were reduced by zonisamide but not by carbamazepine, similar to that of S284L-ADSHE patients. Carbamazepine unaffected functional abnormality in transmission of S286L-TG rats. However, zonisamide was able to compensate for the attenuated S286L-mutant nAChR induced GABA release in frontal-cortex, without affecting attenuated thalamocortical glutamatergic transmission. Excitatory effects of S286L-mutant nAChR on thalamocortical transmission were attenuated compared with those of wild-type nAChR. Loss-of-function of S286L-nAChR enhanced transmission in thalamocortical motor pathway by predominantly attenuating GABAergic transmission. However, it attenuated transmission in thalamocortical cognitive pathway by reducing inhibitory GABAergic and excitatory glutamatergic transmission.Conclusion and implicationsOur results suggest that functional abnormalities of S286L-nAChR are associated with intra-frontal and thalamocortical transmission, possibly contributing to the pathogenesis of ADSHE-seizure and comorbidity of S284L-ADSHE. Selective compensation of impaired GABAergic transmission by zonisamide (but not by carbamazepine) in frontal cortex may be involved, at least partially, in carbamazepine-resistant ADSHE-seizure of S284L-ADSHE patients.

Project description:The endothelium has been established to generate intercellular stresses and suggested to transmit these intercellular stresses through cell-cell junctions, such as VE-Cadherin and ZO-1, for example. Although the previously mentioned molecules reflect the appreciable contributions both adherens junctions and tight junctions are believed to have in endothelial cell intercellular stresses, in doing so they also reveal the obscure relationship that exists between gap junctions and intercellular stresses. Therefore, to bring clarity to this relationship we disrupted expression of the endothelial gap junction connexin 43 (Cx43) by exposing confluent human umbilical vein endothelial cells (HUVECs) to a low (0.2 ?g/mL) and high (2 ?g/mL) concentration of 2,5-dihydroxychalcone (chalcone), a known Cx43 inhibitor. To evaluate the impact Cx43 disruption had on endothelial cell mechanics we utilized traction force microscopy and monolayer stress microscopy to measure cell-substrate tractions and cell-cell intercellular stresses, respectively. HUVEC monolayers exposed to a low concentration of chalcone produced average normal intercellular stresses that were on average 17% higher relative to control, while exposure to a high concentration of chalcone yielded average normal intercellular stresses that were on average 55% lower when compared to control HUVEC monolayers. HUVEC maximum shear intercellular stresses were observed to decrease by 16% (low chalcone concentration) and 66% (high chalcone concentration), while tractions exhibited an almost 2-fold decrease under high chalcone concentration. In addition, monolayer cell velocities were observed to decrease by 19% and 35% at low chalcone and high chalcone concentrations, respectively. Strain energies were also observed to decrease by 32% and 85% at low and high concentration of chalcone treatment, respectively, when compared to control. The findings we present here reveal for the first time the contribution Cx43 has to endothelial biomechanics.

Dataset Information

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 ?4 Subunit of Nicotinic ACh Receptor.

Publications

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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