Pathomechanism of nocturnal paroxysmal dystonia in autosomal dominant sleep-related hypermotor epilepsy with S284L-mutant α4 subunit of nicotinic ACh receptor

Kouji Fukuyama; Masashi Fukuzawa; Takashi Shiroyama; Motohiro Okada

doi:10.1016/j.biopha.2020.110070

Pathomechanism of nocturnal paroxysmal dystonia in autosomal dominant sleep-related hypermotor epilepsy with S284L-mutant α4 subunit of nicotinic ACh receptor

Biomed Pharmacother. 2020 Jun:126:110070. doi: 10.1016/j.biopha.2020.110070. Epub 2020 Mar 10.

Authors

Kouji Fukuyama¹, Masashi Fukuzawa², Takashi Shiroyama³, Motohiro Okada⁴

Affiliations

¹ Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu, Mie 514-8507, Japan. Electronic address: k-fukuyama@clin.medic.mie-u.ac.jp.
² Department of Biology, Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki. 036-8560, Japan. Electronic address: fukuzawa@hirosaki-u.ac.jp.
³ Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu, Mie 514-8507, Japan. Electronic address: takashi@clin.medic.mie-u.ac.jp.
⁴ Department of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu, Mie 514-8507, Japan. Electronic address: okadamot@clin.medic.mie-u.ac.jp.

PMID: 32169758
DOI: 10.1016/j.biopha.2020.110070

Abstract

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.

Keywords: ADSHE; Dystonia; Epilepsy; GABA; L-glutamate; Zonisamide.

MeSH terms

Alleles
Amino Acid Substitution
Animals
Disease Susceptibility
Epilepsy / complications*
Epilepsy / genetics*
Genes, Dominant*
Glutamine / metabolism
Metabolic Networks and Pathways
Mutation*
Nocturnal Paroxysmal Dystonia / etiology*
Nocturnal Paroxysmal Dystonia / metabolism*
Protein Subunits / genetics*
Protein Subunits / metabolism
Receptors, Nicotinic / genetics*
Receptors, Nicotinic / metabolism
Sleep
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
gamma-Aminobutyric Acid / metabolism

Substances

Protein Subunits
Receptors, Nicotinic
Glutamine
gamma-Aminobutyric Acid
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid