Sigma-1 chaperone protein and GABA-B receptor interaction modulates seizure threshold

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain, and, by binding to GABA receptors, it maintains an inhibitory tone that counterbalances neuronal excitation. There is a growing body of evidence that sigma-1 chaperone protein (S1CP) is involved in the modulation of seizures. To evaluate the possible interactions between S1CP and GABA receptors, this study aimed to compare the GABA receptor expression in different brain structures and seizure susceptibility in wild-type and S1CP knockout mice. Quantitative PCR, Western blotting and immunohistochemistry of free-floating sections were used to assess the gene and protein expression of γ2 subunit of GABA-A and R1 and R2 subunit of GABA-B receptor in different brain structures of CD-1 background wild-type and S1CP knockout male mice. Intravenous pentylenetetrazol (PTZ) and (+)-bicuculline (BIC) infusion-induced acute seizure models were used to compare the seizure threshold between wild-type and S1CP knockout animals. Western blotting and immunohistochemistry showed significantly decreased GABA-B R2 protein expression in the Cornu Ammonis 1 area of the hippocampus in S1CP knockout mice. The most significant decrease of staining intensity of the R2 subunit of the GABA-B receptor was found in the ventral part of the medial habenula of S1CP knockout animals. Compared with wild-type mice, S1CP knockout animals were more susceptible to tonic seizures in both PTZ- and BIC-induced seizure models. The tonic seizure threshold was significantly decreased in S1CP knockout animals by 28% and 22%, respectively. Our study demonstrates that S1CP is involved in the balance maintenance between excitation and inhibition through GABA-B-ergic mechanisms and could be used as a valuable target for developing novel antiseizure drugs.Acknowledgments: This study was supported by European Regional Development Fund Project No. 1.1.1.2/VIAA/2/18/376, “Sigma chaperone protein as a novel drug target”. We thank Laboratorios Dr Esteve, S.A. (Barcelona, Spain) for providing CD-1 sigma-1 receptor knockout mice.