Temporal epilepsy: contribution of molecular genetics to epileptogenesis mechanisms
https://doi.org/10.17749/2077-8333/epi.par.con.2025.265
Abstract
Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy. The mechanisms of epileptogenesis in TLE involve a wide range of neurobiological, biochemical, genomic, epigenetic, and transcriptomic changes. Together, these processes lead to morphofunctional reorganization of neural networks and the onset of spontaneous seizures. Neuroinflammation (involving glia activation and cytokine release), neural network remodeling, impaired signal transmission, and loss of inhibitory interneurons play a prominent role in epileptogenesis. Hippocampus transcriptomic studies have revealed a wide range of involved genes, highlighting the importance for interplay between genetic predisposition and acquired factors in developing this disease. The review presents current views on the neurobiological and molecular genetic basis of TLE-related epileptogenesis.
About the Authors
M. Yu. Maksimova
Russian Center of Neurology and Neurosciences
Russian Federation
Russian Federation
Marina Yu. Maksimova, Dr. Sci. Med., Prof.
WoS ResearcherID: C-7408-2012
Scopus Author ID: 7003900736
80 Volokolamskoe Shosse, Moscow 125367
A. M. Teplyshova
Russian Center of Neurology and Neurosciences
Russian Federation
Russian Federation
Anna M. Teplyshova, PhD
80 Volokolamskoe Shosse, Moscow 125367
References
1. Neumann A.M., Britsch S. Molecular genetics of acquired temporal lobe epilepsy. Biomolecules. 2024; 14 (6): 669. https://doi.org/10.3390/biom14060669.
2. Deleu B., Jeuris J., Van Paesschen W. The interacting etiologies of hippocampal sclerosis in epilepsy: a scoping review. Epilepsia. 2025; Oct 17. https://doi.org/10.1111/epi.18676.
3. Piñero J., Ramírez-Anguita J.M., Saüch-Pitarch J., et al. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res. 2020; 48 (D1): D845–55. https://doi.org/10.1093/nar/gkz1021.
4. Łukasiuk K., Lasoń W. Emerging molecular targets for antiepileptogenic and epilepsy modifying drugs. Int J Mol Sci. 2023; 24 (3): 2928. https://doi.org/10.3390/ijms24032928.
5. Zattoni M., Mura M.L., Deprez F., et al. Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy. J Neurosci. 2011; 31 (11): 4037–50. https://doi.org/10.1523/JNEUROSCI.6210-10.2011.
6. Zhu X., Li X., Zhu M., et al. Metalloprotease Adam10 suppresses epilepsy through repression of hippocampal neuroinflammation. J Neuroinflammation. 2018; 15 (1): 221. https://doi.org/10.1186/s12974-018-1260-z.
7. Ammothumkandy A., Ravina K., Wolseley V., et al. Altered adult neurogenesis and gliogenesis in patients with mesial temporal lobe epilepsy. Nat Neurosci. 2022; 25 (4): 493–503. https://doi.org/10.1038/s41593-022-01044-2.
8. Patel D.C., Tewari B.P., Chaunsali L., Sontheimer H. Neuron-glia interactions in the pathophysiology of epilepsy. Nat Rev Neurosci. 2019; 20 (5): 282–97. https://doi.org/10.1038/s41583-019-0126-4.
9. Robel S., Buckingham S.C., Boni J.L., et al. Reactive astrogliosis causes the development of spontaneous seizures. J Neurosci. 2015; 35 (8): 3330–45. https://doi.org/10.1523/jneurosci.1574-14.2015.
10. Liu X.X., Yang L., Shao L.X., et al. Endothelial Cdk5 deficit leads to the development of spontaneous epilepsy through CXCL1/CXCR2-mediated reactive astrogliosis. J Exp Med. 2020; 217 (1): e20180992. https://doi.org/10.1084/jem.20180992.
11. Zhang M.W., Liang X.Y., Wang J., et al. Epilepsy-associated genes: an update. Seizure. 2024; 116: 4–13. https://doi.org/10.1016/j.seizure.2023.09.021.
12. Buckmaster P.S., Abrams E., Wen X. Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy. J Comp Neurol. 2017; 525 (11): 2592–610. https://doi.org/10.1002/cne.24226.
13. Hunt R.F., Girskis K.M., Rubenstein J.L., et al. GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. Nat Neurosci. 2013; 16 (6): 692–7. https://doi.org/10.1038/nn.3392.
14. Drexel M., Romanov R.A., Wood J., et al. selective silencing of hippocampal parvalbumin interneurons induces development of recurrent spontaneous limbic seizures in mice. J Neurosci. 2017; 37 (34): 8166–79. https://doi.org/10.1523/JNEUROSCI.3456-16.2017.
15. Tan G.H., Liu Y.Y., Hu X.L., et al. Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons. Nat Neurosci. 2011; 15 (2): 258–66. https://doi.org/10.1038/nn.3005.
16. Thind K.K., Yamawaki R., Phanwar I., et al. Initial loss but later excess of GABAergic synapses with dentate granule cells in a rat model of temporal lobe epilepsy. J Comp Neurol. 2010; 518 (5): 647–67. https://doi.org/10.1002/cne.22235.
17. Miri M.L., Vinck M., Pant R., Cardin J.A. Altered hippocampal interneuron activity precedes ictal onset. Elife. 2018; 7: e40750. https://doi.org/10.7554/eLife.40750.
18. Kjær C., Barzaghi G., Bak L.K., et al. Transcriptome analysis in patients with temporal lobe epilepsy. Brain. 2019; 142 (10): e55. https://doi.org/10.1093/brain/awz265.
19. Zhang W., Wang H., Liu B., et al. Differential DNA methylation profiles in patients with temporal lobe epilepsy and hippocampal sclerosis ILAE type I. J Mol Neurosci. 2021; 71 (9): 1951–66. https://doi.org/10.1007/s12031-020-01780-9.
20. Meng X.F., Yu J.T., Song J.H., et al. Role of the mTOR signaling pathway in epilepsy. J Neurol Sci. 2013; 332 (1-2): 4–15. https://doi.org/10.1016/j.jns.2013.05.029.
21. Nguyen L.H., Mahadeo T., Bordey A. mTOR hyperactivity levels influence the severity of epilepsy and associated neuropathology in an experimental model of tuberous sclerosis complex and focal cortical dysplasia. J Neurosci. 2019; 39 (14): 2762–73. https://doi.org/10.1523/JNEUROSCI.2260-18.2019.
22. Pun R.Y., Rolle I.J., Lasarge C.L., et al. Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy. Neuron. 2012; 75 (6): 1022–34. https://doi.org/10.1016/j.neuron.2012.08.002.
23. LaSarge C.L., Pun R.Y.K., Gu Z., et al. mTOR-driven neural circuit changes initiate an epileptogenic cascade. Prog Neurobiol. 2021; 200: 101974. https://doi.org/10.1016/j.pneurobio.2020.101974.
24. Khoshkhoo S., Wang Y., Chahine Y., et al. Contribution of somatic Ras/Raf/mitogen-activated protein kinase variants in the hippocampus in drug-resistant mesial temporal lobe epilepsy. JAMA Neurol. 2023; 80 (6): 578–87. https://doi.org/10.1001/jamaneurol.2023.0473.
25. McNamara J.O., Scharfman H.E. Temporal lobe epilepsy and the BDNF receptor, TrkB. In: Noebels J.L., Avoli M., Rogawski M.A., et al. (Eds). Jasper's basic mechanisms of the epilepsies. 4th ed. New York: Oxford University Press; 2024: 1264 pp.
26. Lin T.W., Harward S.C., Huang Y.Z., McNamara J.O. Targeting BDNF/TrkB pathways forpreventing or suppressing epilepsy. Neuropharmacology. 2020; 167: 107734. https://doi.org/10.1016/j.neuropharm.2019.107734.
27. Harward S.C., Huang Y.Z., McNamara J.O. BDNF/TrkB signaling and epileptogenesis. In: Noebels J.L., Avoli M., Rogawski M.A., et al. (Eds). Jasper's basic mechanisms of the epilepsies. 5th ed. New York: Oxford University Press; 2024: 1752 pp.
28. Marballi K., MacDonald J.L. Proteomic and transcriptional changes associated with MeCP2 dysfunction reveal nodes for therapeutic intervention in Rett syndrome. Neurochem Int. 2021; 148: 105076. https://doi.org/10.1016/j.neuint.2021.105076.
29. Collins B.E., Neul J.L. Rett syndrome and MECP2 duplication syndrome: disorders of MeCP2 dosage. Neuropsychiatr Dis Treat. 2022; 18: 2813–35. https://doi.org/10.2147/NDT.S371483.
30. Yi Z., Yang W., Ma Y., et al. Characterization of the relationship of CDKL5 with MeCP2 and Dnmt1 in primary rat cortical neurons. Braz Arch Biol Technol. 2016; 59. https://doi.org/10.1590/1678-4324-2016150510.
31. Ehinger Y., Bruyère J., Panayotis N., et al. Huntingtin phosphorylation governs BDNF homeostasis and improves the phenotype of Mecp2 knockout mice. EMBO Mol Med. 2020; 12 (2): e10889. https://doi.org/10.15252/emmm.201910889.
32. Zhang L., He J., Jugloff D.G., Eubanks J.H. The MeCP2-null mouse hippocampus displays altered basal inhibitory rhythms and is prone to hyperexcitability. Hippocampus. 2008; 18 (3): 294–309. https://doi.org/10.1002/hipo.20389.
33. Tao S., Yang X., Chen Y., et al. Up-regulated methyl CpG binding protein-2 in intractable temporal lobe epilepsy patients and a rat model. Neurochem Res. 2012; 37 (9): 1886–97. https://doi.org/10.1007/s11064-012-0804-3.
34. Meshkinkhood N., Barati Dowom P., Noorbakhsh F., et al. Unveiling molecular dynamics of MeCp2, CDKL5 and BDNF in the hippocampus of individuals with intractable mesial temporal lobe epilepsy. J Cell Mol Med. 2025; 29 (3): e70373. https://doi.org/10.1111/jcmm.70373.
35. Dogini D.B., Avansini S.H., Vieira A.S., Lopes-Cendes I. MicroRNA regulation and dysregulation in epilepsy. Front Cell Neurosci. 2013; 7: 172. https://doi.org/10.3389/fncel.2013.00172.
36. Siegel G., Saba R., Schratt G. MicroRNAs in neurons: manifold regulatory roles at the synapse. Curr Opin Genet Dev. 2011; 21 (4): 491–7. https://doi.org/10.1016/j.gde.2011.04.008.
37. Letellier M., Elramah S., Mondin M., et al. miR-92a regulates expression of synaptic GluA1-containing AMPA receptors during homeostatic scaling. Nat Neurosci. 2014; 17 (8): 1040–2. https://doi.org/10.1038/nn.3762.
38. Aronica E., Fluiter K., Iyer A., et al. Expression pattern of miR-146a, an inflammation-associated microRNA, in experimental and human temporal lobe epilepsy. Eur J Neurosci. 2010; 31 (6): 1100–7. https://doi.org/10.1111/j.1460-9568.2010.07122.x.
39. Iyer A., Zurolo E., Prabowo A., et al. MicroRNA-146a: a key regulator of astrocyte-mediated inflammatory response. PLoS One. 2012; 7 (9): e44789. https://doi.org/10.1371/journal.pone.0044789.
40. Reschke C.R., Henshall D.C. MicroRNA and epilepsy. Adv Exp Med Biol. 2015; 888: 41–70. https://doi.org/10.1007/978-3-319-22671-2_4.
41. Simon R., Wiegreffe C., Britsch S. Bcl11 transcription factors regulate cortical development and function. Front Mol Neurosci. 2020; 13: 51. https://doi.org/10.3389/fnmol.2020.00051.
42. Jain S., Zipursky S. Temporal control of neuronal wiring. Semin Cell Dev Biol. 2023; 142: 81–90. https://doi.org/10.1016/j.semcdb.2022.05.012.
43. Lösing P., Niturad C.E., Harrer M., et al. SRF modulates seizure occurrence, activity induced gene transcription and hippocampal circuit reorganization in the mouse pilocarpine epilepsy model. Mol Brain. 2017; 10 (1): 30. https://doi.org/10.1186/s13041-017-0310-2.
44. Zhu X., Dubey D., Bermudez C., Porter B.E. Suppressing cAMP response element-binding protein transcription shortens the duration of status epilepticus and decreases the number of spontaneous seizures in the pilocarpine model of epilepsy. Epilepsia. 2015; 56 (12): 1870–8. https://doi.org/10.1111/epi.13211.
45. Engel T., Sanz-Rodgriguez A., Jimenez-Mateos E.M., et al. CHOP regulates the p53-MDM2 axis and is required for neuronal survival after seizures. Brain. 2013; 136 (Pt 2): 577–92. https://doi.org/10.1093/brain/aws337.
46. Cai M., Lin W. Тhe function of NF-kappa B during epilepsy, a potential therapeutic target. Front Neurosci. 2022; 16: 851394. https://doi.org/10.3389/fnins.2022.851394.
47. Lubin F.D., Ren Y., Xu X., Anderson A.E. Nuclear factor-kappa B regulates seizure threshold and gene transcription following convulsant stimulation. J Neurochem. 2007; 103 (4): 1381–95. https://doi.org/10.1111/j.1471-4159.2007.04863.x.
48. Mazzuferi M., Kumar G., van Eyll J., et al. Nrf2 defense pathway: experimental evidence for its protective role in epilepsy. Ann Neurol. 2013; 74 (4): 560–8. https://doi.org/10.1002/ana.23940.
49. Dreier J.W., Ellis C.A., Berkovic S.F., et al. Epilepsy risk in offspring of affected parents; a cohort study of the “maternal effect” in epilepsy. Ann Clin Transl Neurol. 2021; 8 (1): 153–62. https://doi.org/10.1002/acn3.51258.
50. Oliver K.L., Ellis C.A., Scheffer I.E., et al. Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery. EBioMedicine. 2022; 81: 104079. https://doi.org/10.1016/j.ebiom.2022.104079.
51. Silvennoinen K., Gawel K., Tsortouktzidis D., et al. SCN1A overexpression, associated with a genomic region marked by a risk variant for a common epilepsy, raises seizure susceptibility. Acta Neuropathol. 2022; 144 (1): 107–27. https://doi.org/10.1007/s00401-022-02429-0.
52. Kasperaviciute D., Catarino C.B., Matarin M., et al. Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A. Brain. 2013; 136 (Pt 10): 3140–50. https://doi.org/10.1093/brain/awt233.
53. Skotte L., Fadista J., Bybjerg-Grauholm J., et al. Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes. Brain. 2022; 145 (2): 555–68. https://doi.org/10.1093/brain/awab260.
54. Riney K., Bogacz A., Somerville E., et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset at a variable age: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022; 63 (6): 1443–74. https://doi.org/10.1111/epi.17240.
55. Striano P., Serioli E., Santulli L., et al. DEPDC5 mutations are not a frequent cause of familial temporal lobe epilepsy. Epilepsia. 2015; 56 (10): e168–71. https://doi.org/10.1111/epi.13094.
56. Dazzo E., Fanciulli M., Serioli E., et al. Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy. Am J Hum Genet. 2015; 96 (6): 992–1000. https://doi.org/10.1016/j.ajhg.2015.04.020.
57. Yang H., Yin F., Gan S., et al. The study of genetic susceptibility and mitochondrial dysfunction in mesial temporal lobe epilepsy. Mol Neurobiol. 2020; 57 (9): 3920–30. https://doi.org/10.1007/s12035- 020-01993-4.
58. Thakran S., Guin D., Singh P., et al. Genetic landscape of common epilepsies: advancing towards precision in treatment. Int J Mol Sci. 2020; 21 (20): 7784. https://doi.org/10.3390/ijms21207784.
Review
For citations:
Maksimova M.Yu., Teplyshova A.M. Temporal epilepsy: contribution of molecular genetics to epileptogenesis mechanisms. Epilepsy and paroxysmal conditions. 2025;17(4):402-409. (In Russ.) https://doi.org/10.17749/2077-8333/epi.par.con.2025.265
Views:
17
JATS XML
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Email this article 
