Molecular Signaling Pathways involved in Temporal Lobe Epilepsy

Document Type : Review article

Authors

1 Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.

2 Department of Clinical Biochemistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 Department of Anatomy, Tehran University of Medical Sciences, Tehran, Iran.

4 Department of Neuroscience, Mashhad University of Medical Science, Mashhad, Iran

Abstract

Epilepsy is a chronic neurological disorder that defined as a disorder of recurrent seizures and characterized by an imbalance of excitation and inhibition in the brain. Despite many efforts in recent years, one-third of the epileptic patients are refractory to medical treatment.  It has been reported that genetic factors, synaptic ion channels, excitatory and inhibitory neurotransmitters and activation of various receptors such as ionotropic and metabotropic glutamate receptors in the central nervous system can promote epileptogenesis. Further research to investigate the molecular mechanisms and ions involved in the development of epilepsy is needed. In this review, we present an overview of current status into the molecular signaling pathways involved in epileptogenesis. Furthermore, we will focus on temporal lobe epilepsy (TLE) molecular mechanisms. Understanding of molecular mechanisms could provide new fascinating insights into drug target identification in the prevention of epileptogenesis.
 

Keywords


1.            Magiorkinis E, Sidiropoulou K, Diamantis A. Hallmarks in the history of epilepsy: epilepsy in antiquity. Epilepsy Behav. 2010;17(1):103-8.
2.            Staley K. Molecular mechanisms of epilepsy. Nat Neurosci. 2015;18(3):367-72.
3.            Thurman DJ, Beghi E, Begley CE, Berg AT, Buchhalter JR, Ding D, et al. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia. 2011;52(s7):2-26.
4.            Fisher RS, Boas WvE, Blume W, Elger C, Genton P, Lee P, et al. Epileptic Seizures and Epilepsy: Definitions Proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005;46(4):470-2.
5.            McNamara JO, Huang YZ, Leonard AS. Molecular signaling mechanisms underlying epileptogenesis. Sci Stke. 2006;356:12.
6.            epilepsies Pfrco, syndromes e. Commission on classification and terminology of the International League Against Epilepsy. Epilepsia. 1989;30:389-99.
7.            Meencke HJ, Janz D. Neuropathological Findings in Primary Generalized Epilepsy: A Study of Eight Cases. Epilepsia. 1984;25(1):8-21.
8.            Seneviratne U, Woo JJ, Boston RC, Cook M, D'Souza W. Focal seizure symptoms in idiopathic generalized epilepsies. Neurology. 2015;85(7):589-95.
9.            Trinka E, Cock H, Hesdorffer D, Rossetti AO, Scheffer IE, Shinnar S, et al. A definition and classification of status epilepticus–Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015;56(10):1515-23.
10.          Steinlein OK. Genetic mechanisms that underlie epilepsy. Nature Reviews Neuroscience. 2004;5(5):400-8.
11.          Steinlein OK, Mulley JC, Propping P, Wallace RH, Phillips HA, Sutherland GR, et al. A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 1995;11(2):201-3.
12.          Baulac S, Huberfeld G, Gourfinkel-An I, Mitropoulou G, Beranger A, Prud'homme J-F, et al. First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the γ2-subunit gene. Nat Genet. 2001;28(1):46-8.
13.          Wallace RH, Marini C, Petrou S, Harkin LA, Bowser DN, Panchal RG, et al. Mutant GABAA receptor γ2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet. 2001;28(1):49-52.
14.          Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31(2):184-9.
15.          Wallace RH, Wang DW, Singh R, Scheffer IE, George AL, Phillips HA, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel ß1 subunit gene SCN1B. Nat Genet. 1998;19(4):366-70.
16.          Sugawara T, Tsurubuchi Y, Agarwala KL, Ito M, Fukuma G, Mazaki-Miyazaki E, et al. A missense mutation of the Na+ channel αII subunit gene Nav1. 2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proceedings of the National Academy of Sciences. 2001;98(11):6384-9.
17.          Haug K, Warnstedt M, Alekov AK, Sander T, Ramírez A, Poser B, et al. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet. 2003;33(4):527-32.
18.          Singh NA, Charlier C, Stauffer D, DuPont BR, Leach RJ, Melis R, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet. 1998;18(1):25-9.
19.          Biervert C, Schroeder BC, Kubisch C, Berkovic SF, Propping P, Jentsch TJ, et al. A potassium channel mutation in neonatal human epilepsy. Science. 1998;279(5349):403-6.
20.          Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev. 1999;51(1):7-62.
21.          Kullmann D, Asztely F, Walker M. The role of mammalian ionotropic receptors in synaptic plasticity: LTP, LTD and epilepsy. Cellular and Molecular Life Sciences CMLS. 2000;57(11):1551-61.
22.          Lisman J, Yasuda R, Raghavachari S. Mechanisms of CaMKII action in long-term potentiation. Nature Reviews Neuroscience. 2012;13(3):169-82.
23.          Wang A, Chi Z, Wang S, Wang S, Sun Q. Calcineurin-mediated GABA A receptor dephosphorylation in rats after kainic acid-induced status epilepticus. Seizure. 2009;18(7):519-23.
24.          Ben-Ari Y, Cossart R. Kainate, a double agent that generates seizures: two decades of progress. Trends Neurosci. 2000;23(11):580-7.
25.          Schinder AF, Poo M-m. The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci. 2000;23(12):639-45.
26.          Binder DK, Croll SD, Gall CM, Scharfman HE. BDNF and epilepsy: too much of a good thing? Trends Neurosci. 2001;24(1):47-53.
27.          Minichiello L. TrkB signalling pathways in LTP and learning. Nature Reviews Neuroscience. 2009;10(12):850-60.
28.          Kaplan DR, Miller FD. Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol. 2000;10(3):381-91.
29.          Huang EJ, Reichardt LF. Trk receptors: roles in neuronal signal transduction*. Annu Rev Biochem. 2003;72(1):609-42.
30.          Kouhara H, Hadari Y, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, et al. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell. 1997;89(5):693-702.
31.          Reichardt LF. Neurotrophin-regulated signalling pathways. Philosophical Transactions of the Royal Society of London B: Biological Sciences. 2006;361(1473):1545-64.
32.          Devinsky O, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA. Glia and epilepsy: excitability and inflammation. Trends Neurosci. 2013;36(3):174-84.
33.          de Lanerolle NC, Lee T-S, Spencer DD. Astrocytes and epilepsy. Neurotherapeutics. 2010;7(4):424-38.
34.          Khurgel M, Ivy GO. Astrocytes in kindling: relevance to epileptogenesis. Epilepsy Res. 1996;26(1):163-75.
35.          David Y, Cacheaux LP, Ivens S, Lapilover E, Heinemann U, Kaufer D, et al. Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis? The Journal of Neuroscience. 2009;29(34):10588-99.
36.          Seifert G, Steinhäuser C. Neuron–astrocyte signaling and epilepsy. Experimental neurology. 2013;244:4-10.
37.          Bozzi Y, Borrelli E. The role of dopamine signaling in epileptogenesis. Neuronal mechanisms of epileptogenesis. 2015.
38.          Starr MS. The role of dopamine in epilepsy. Synapse. 1996;22(2):159-94.
39.          Galanopoulou AS. GABAA receptors in normal development and seizures: friends or foes? Curr Neuropharmacol. 2008;6(1):1-20.
40.          Mares P, Kubova H. What is the role of neurotransmitter systems in cortical seizures? Physiol Res. 2008;57:S111.
41.          Theodore WH. Does serotonin play a role in epilepsy? Epilepsy Curr. 2003;3(5):173-7.
42.          Bagdy G, Kecskemeti V, Riba P, Jakus R. Serotonin and epilepsy. J Neurochem. 2007;100(4):857-73.
43.          Trimble MR. Serum prolactin in epilepsy and hysteria. Br Med J. 1978;2(6153):1682-.
44.          Banerjee S, Paul P, Talib V. Serum prolactin in seizure disorders. Indian Pediatr. 2004;41(8):827-30.
45.          Rezaei M, Sadeghian A, Roohi N, Shojaei A, Mirnajafi-Zadeh J. Epilepsy and dopaminergic system. Physiology and Pharmacology. 2017;21(1):1-14.
46.          Ran X, Li J, Shao Q, Chen H, Lin Z, Sun ZS, et al. EpilepsyGene: a genetic resource for genes and mutations related to epilepsy. Nucleic Acids Res. 2014:gku943.