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

Funding Information: This study was supported by European Regional Development Fund Project No. 1.1.1.2/VIAA/2/18/376 (PostDoc Latvia), “Sigma chaperone protein as a novel drug target”. We thank Laboratorios Dr. Esteve, S.A. (Barcelona, Spain) for providing CD-1 background sigma-1 receptor knockout mice. We thank Associate Professors Inga Kadisha and Thomas van Groen (University of Alabama at Birmingham, Birmingham, Alabama, USA) for fruitful discussions regarding immunohistochemistry. We also thank Dr. biol. Dace Pjanova (Latvian Biomedical Research and Study Centre, Riga, Latvia) for the help with confocal imaging and Abberior Instruments (Göttingen, Germany) for a kind gift of fluorescently labeled Abberior STAR antibodies. Publisher Copyright: © 2020 The Author(s)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.publishersversionPeer reviewe

Reduced GFAP expression in Bergmann glial cells in the cerebellum of sigma-1 receptor knockout mice determines the neurobehavioral outcomes after traumatic brain injury

Funding Information: Funding: This study was supported by EU-ERA-NET NEURON project TRAINS No. 9642151 and the European Union’s Horizon 2020 research and innovation program under grant agreement No. 857394. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Neuroprotective effects of Sigma-1 receptor (S1R) ligands have been observed in multiple animal models of neurodegenerative diseases. Traumatic brain injury (TBI)-related neurodegeneration can induce long-lasting physical, cognitive, and behavioral disabilities. The aim of our study was to evaluate the role of S1R in the development of neurological deficits after TBI. Adult male wild-type CD-1 (WT) and S1R knockout (S1R-/-) mice were subjected to lateral fluid percussion injury, and behavioral and histological outcomes were assessed for up to 12 months postinjury. Neurological deficits and motor coordination impairment were less pronounced in S1R-/-mice with TBI than in WT mice with TBI 24 h after injury. TBI-induced short-term memory impairments were present in WT but not S1R-/-mice 7 months after injury. Compared to WT animals, S1R-/-mice exhibited better motor coordination and less pronounced despair behavior for up to 12 months postinjury. TBI induced astrocyte activation in the cortex of WT but not S1R-/-mice. S1R-/-mice presented a significantly reduced GFAP expression in Bergmann glial cells in the molecular layer of the cerebellum compared to WT mice. Our findings suggest that S1R deficiency reduces TBI-induced motor coordination impairments by reducing GFAP expression in Bergmann glial cells in the cerebellum.publishersversionPeer reviewe