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Genetic inactivation of the sigma-1 chaperone protein results in decreased expression of the R2 subunit of the GABA-B receptor and increased susceptibility to seizures.
- Source :
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Neurobiology of Disease . Mar2021, Vol. 150, pN.PAG-N.PAG. 1p. - Publication Year :
- 2021
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Abstract
- There is a growing body of evidence demonstrating the significant involvement of the sigma-1 chaperone protein in the modulation of seizures. Several sigma-1 receptor (Sig1R) ligands have been demonstrated to regulate the seizure threshold in acute and chronic seizure models. However, the mechanism by which Sig1R modulates the excitatory and inhibitory pathways in the brain has not been elucidated. The aim of this study was to compare the susceptibility to seizures of wild type (WT) and Sig1R knockout (Sig1R−/−) mice in intravenous pentylenetetrazol (PTZ) and (+)-bicuculline (BIC) infusion-induced acute seizure and Sig1R antagonist NE-100-induced seizure models. To determine possible molecular mechanisms, we used quantitative PCR, Western blotting and immunohistochemistry to assess the possible involvement of several seizure-related genes and proteins. Peripheral tissue contractile response of WT and Sig1R−/− mice was studied in an isolated vasa deferentia model. The most important finding was the significantly decreased expression of the R2 subunit of the GABA-B receptor in the hippocampus and habenula of Sig1R−/− mice. Our results demonstrated that Sig1R−/− mice have decreased thresholds for PTZ- and BIC-induced tonic seizures. In the NE-100-induced seizure model, Sig1R−/− animals demonstrated lower seizure scores, shorter durations and increased latency times of seizures compared to WT mice. Sig1R-independent activities of NE-100 included downregulation of the gene expression of iNOS and GABA-A γ2 and inhibition of KCl-induced depolarization in both WT and Sig1R−/− animals. In conclusion, the results of this study indicate that the lack of Sig1R resulted in decreased expression of the R2 subunit of the GABA-B receptor and increased susceptibility to seizures. Our results confirm that Sig1R is a significant molecular target for seizure modulation and warrants further investigation for the development of novel anti-seizure drugs. Unlabelled Image • Sig1R−/− mice demonstrate decreased expression of the R2 subunit of the GABA-B receptor in the ventral part of the medial habenula. • Sig1R−/− mice are more susceptible to pentylenetetrazol- and (+)bicuculline-induced seizures. • Sig1R antagonist NE-100 demonstrates Sig1R-independent effects. • NE-100-induced seizure severity is significantly less pronounced in Sig1R−/− mice. • Sig1R is a valuable target for the development of novel anti-seizure drugs. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 09699961
- Volume :
- 150
- Database :
- Academic Search Index
- Journal :
- Neurobiology of Disease
- Publication Type :
- Academic Journal
- Accession number :
- 148546353
- Full Text :
- https://doi.org/10.1016/j.nbd.2020.105244