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Open AccessCommunication

Changes in Calcium Homeostasis and Gene Expression Implicated in Epilepsy in Hippocampi of Mice Overexpressing ORAI1

1
Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw, Trojdena 4, 02-109 Warsaw, Poland
2
Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, PAS, Pasteura 3, 02-093 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Ph.D. student at the Postgraduate School of Molecular Medicine, Warsaw Medical University, 61 Żwirki i Wigury St., 02-091 Warsaw, Poland.
Int. J. Mol. Sci. 2019, 20(22), 5539; https://doi.org/10.3390/ijms20225539
Received: 30 September 2019 / Revised: 4 November 2019 / Accepted: 4 November 2019 / Published: 6 November 2019
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)
Previously, we showed that the overexpression of ORAI1 calcium channel in neurons of murine brain led to spontaneous occurrence of seizure-like events in aged animals of transgenic line FVB/NJ-Tg(ORAI1)Ibd (Nencki Institute of Experimental Biology). We aimed to identify the mechanism that is responsible for this phenomenon. Using a modified Ca2+-addback assay in the CA1 region of acute hippocampal slices and FURA-2 acetomethyl ester (AM) Ca2+ indicator, we found that overexpression of ORAI1 in neurons led to altered Ca2+ response. Next, by RNA sequencing (RNAseq) we identified a set of genes, whose expression was changed in our transgenic animals. These data were validated using customized real-time PCR assays and digital droplet PCR (ddPCR) ddPCR. Using real-time PCR, up-regulation of hairy and enhancer of split-5 (Hes-5) gene and down-regulation of aristaless related homeobox (Arx), doublecortin-like kinase 1 (Dclk1), and cyclin-dependent kinase-like 5 (Cdkl5, also known as serine/threonine kinase 9 (Stk9)) genes were found. Digital droplet PCR (ddPCR) analysis revealed down-regulation of Arx. In humans, ARX, DCLK1, and CDLK5 were shown to be mutated in some rare epilepsy-associated disorders. We conclude that the occurrence of seizure-like events in aged mice overexpressing ORAI1 might be due to the down-regulation of Arx, and possibly of Cdkl5 and Dclk1 genes. View Full-Text
Keywords: epileptic seizures; ORAI1; STIM1; STIM2; nSOCE; RNAseq; RT-PCR; Cdkl5; Arx; Dclk1 epileptic seizures; ORAI1; STIM1; STIM2; nSOCE; RNAseq; RT-PCR; Cdkl5; Arx; Dclk1
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MDPI and ACS Style

Majewski, L.; Wojtas, B.; Maciąg, F.; Kuznicki, J. Changes in Calcium Homeostasis and Gene Expression Implicated in Epilepsy in Hippocampi of Mice Overexpressing ORAI1. Int. J. Mol. Sci. 2019, 20, 5539.

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