Parallel changes in the promoter methylation of voltage-gated T-type calcium channel alpha 1 subunit G and histone deacetylase activity in the WAG/Rij model of absence epilepsy

Year 2023, , 92 - 98, 12.01.2023

Zülfinaz Betül Çelik , Emre Soner Tiryaki , Elif Türkdönmez , M. Nusret Çiçekli , Ahmet Altun , Caner Günaydın

https://doi.org/10.32322/jhsm.1207399

Abstract

Objective: In the last two decades, research on epigenetic mechanisms has expanded dramatically. Recent studies demonstrated that epigenetic mechanisms regulate epilepsy and epileptogenic pathologies. In this study, we aimed to investigate changes in the promoter methylation status of the voltage-gated T-type calcium channel alpha 1 subunit G (CACNA1G) gene and total histone deacetylase activity in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats which is one of the commonly used genetic absence rat models of epilepsy in the three different age groups (3, 6, and 9 months old) on both sexes.
Material and Method: Evaluation of changes in the spike-wave discharges (SWDs) was performed with electrocorticography (ECoG). The promoter methylation status of the CACNA1G gene was determined by methylation-specific PCR (MSP), and histone deacetylase (HDAC) activity was determined spectrophotometrically.
Results: Our results demonstrated that the number of SWDs increased age-dependent in WAG/Rij. Additionally, it was observed that CACNA1G promoter methylation decreased, and total HDAC activity increased with age in both sexes.
Conclusion: Our results provide further support for epigenetic regulation in the absence epilepsy phenotype and suggest that the underlying mechanism behind the increase in the number of SWDs with age in the WAG/Rij animals might be regulated by CACNA1G promoter methylation or HDAC activity.

Keywords

Epilepsy, voltage-gated T-type calcium channel, histone deacetylation, methylation, electrocorticography

Supporting Institution

None.

Project Number

None.

References

• van Luijtelaar G, van Oijen G. Establishing Drug Effects on Electrocorticographic Activity in a Genetic Absence Epilepsy Model: Advances and Pitfalls. Front. Pharmacol 2020; 11: 395.
• Ollivier ML, Dubois MF, Krajinovic M, Cossette P, Carmant L. Risk factors for valproic acid resistance in childhood absence epilepsy. Seizure 2009; 18: 690-4.
• Sarkisova K, van Luijtelaar G. The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 854-76.
• Coenen AML, van Luijtelaar ELJM. Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats. Behav Genet 2003; 33: 635-55.
• Carney PW, Jackson GD. Insights into the mechanisms of absence seizure generation provided by EEG with functional MRI. Front Neurol 2014; 5: 162.
• Abderemane-Ali F, Findeisen F, Rossen ND, Minor Jr DL. A selectivity filter gate controls voltage-gated calcium channel calcium-dependent inactivation. Neuron 2019; 101: 1134-49.
• Weiss N, Zamponi GW. T-type calcium channels: from molecule to therapeutic opportunities. Int J Biochem Cell Biol 2019; 108: 34-9.
• Noebels JL. Calcium channel “gaiting” and absence epilepsy. Epilepsy Curr 2005; 5: 95-7.
• Glaba P, Latka M, Krause MJ, et al. Changes in interictal pretreatment and posttreatment EEG in childhood absence epilepsy. Front Neurosci 2020; 14: 196.
• Imbrici P. Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain 2004;127: 2682-92.
• Ernst WL, Zhang Y, Yoo JW, Ernst SJ, Noebels JL. Genetic enhancement of thalamocortical network activity by elevating 1G-mediated low-voltage-activated calcium current induces pure absence epilepsy. J Neurosci 2009; 29: 1615-25.
• Lazarini-Lopes W, Campos-Rodriguez C, Palmer D, N’Gouemo P, Garcia-Cairasco N, Forcelli PA. Absence epilepsy in male and female WAG/Rij rats: a longitudinal EEG analysis of seizure expression. Epilepsy Res 2021; 176: 106693.
• Araki Y, Mimura T. The mechanisms underlying chronic inflammation in rheumatoid arthritis from the perspective of the epigenetic landscape. J Immunol Res 2016: 1-11.
• Araki Y, Mimura T. The histone modification code in the pathogenesis of autoimmune diseases. Mediators Inflamm 2017: 1-13.
• Percie du Sert N, Hurst V, Ahluwalia A, et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. BMC Vet Res 2020; 16: 242.
• Doğan E, Aygün H, Arslan G, et al. The role of NMDA receptors in the effect of purinergic P2X7 receptor on spontaneous seizure activity in WAG/Rij rats with genetic absence epilepsy. Front Neurosci 2020; 14: 414.
• Santos VR, Kobayashi I, Hammack R, Danko G, Forcelli PA. Impact of strain, sex, and estrous cycle on gamma butyrolactone-evoked absence seizures in rats. Epilepsy Res 2018; 147: 62-70.
• Zhang S, Zhu Y, Cheng J, Tao J. Ion channels in epilepsy: blasting fuse for neuronal hyperexcitability. Epilepsy-Advances in Diagnosis and Therapy 2019: 1-12.
• Noebels JL. The voltage-gated calcium channel and absence epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds. Jasper's basic mechanisms of the epilepsies. Bethesda (MD): 2012.
• Wong M. Too much inhibition leads to excitation in absence epilepsy. Epilepsy Curr 2010; 10: 131-3.
• Caramaschi D, Hatcher C, Mulder RH, et al. Epigenome-wide association study of seizures in childhood and adolescence. Clin Epigenetics 2020; 12: 1.
• Henshall DC, Kobow K. Epigenetics and Epilepsy. Cold Spring Harb Perspect Med 2015; 5: a022731.
• Kobow K, Kaspi A, Harikrishnan KN, et al. Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathol. 2013; 126: 741-56.
• Hauser RM, Henshall DC, Lubin FD. The epigenetics of epilepsy and its progression. Neuroscientist 2017; 24: 186-200.
• Romoli M, Mazzocchetti P, D'Alonzo R, et al. Valproic acid and epilepsy: from molecular mechanisms to clinical evidences. Curr Neuropharmacol 2019; 17: 926-46.
• Damaj L, Lupien-Meilleur A, Lortie A, et al. CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms. Eur J Hum Genet 2015; 23: 1505-12.
• Han L, Xu G, Xu C, Liu B, Liu D. Potential prognostic biomarkers identified by DNA methylation profiling analysis for patients with lung adenocarcinoma. Oncol Lett 2018; 15: 3552-7.
• García-Baquero R, Puerta P, Beltran M, et al. Methylation of a novel panel of tumor suppressor genes in urine moves forward noninvasive diagnosis and prognosis of bladder cancer: a 2-center prospective study. Urol J 2013; 190: 723-30.
• Citraro R, Leo A, De Caro C, et al. Effects of histone deacetylase inhibitors on the development of epilepsy and psychiatric comorbidity in WAG/Rij rats. Mol Neurobiol 2019; 57: 408-21.
• De Caro C, Di Cesare Mannelli L, Branca JJV, et al. Pain modulation in WAG/Rij epileptic rats (a genetic model of absence epilepsy): effects of biological and pharmacological histone deacetylase inhibitors. Front Pharmacol 2020; 11: 549191.