Abstract
Epileptogenesis refers to the process in which a normal brain becomes epileptic, and is characterized by hypersynchronous spontaneous recurrent seizures involving a complex epileptogenic network. Current available pharmacological treatment of epilepsy is generally symptomatic in controlling seizures but is not disease-modifying in epileptogenesis. Cumulative evidence suggests that adult neurogenesis, specifically in the subgranular zone of the hippocampal dentate gyrus, is crucial in epileptogenesis. In this review, we describe the pathological changes that occur in adult neurogenesis in the epileptic brain and how adult neurogenesis is involved in epileptogenesis through different interventions. This is followed by a discussion of some of the molecular signaling pathways involved in regulating adult neurogenesis, which could be potential druggable targets for epileptogenesis. Finally, we provide perspectives on some possible research directions for future studies.
Keywords: Epileptogenesis, adult neurogenesis, drug target, optogenetic, chemogenetic, neural circuit.
Graphical Abstract
[http://dx.doi.org/10.1038/nrdp.2018.24] [PMID: 29722352]
[http://dx.doi.org/10.1016/S0140-6736(18)32596-0] [PMID: 30686584]
[http://dx.doi.org/10.1016/j.pharmthera.2019.05.010] [PMID: 31128154]
[http://dx.doi.org/10.1126/science.135.3509.1127] [PMID: 13860748]
[http://dx.doi.org/10.1038/3305] [PMID: 9809557]
[http://dx.doi.org/10.1073/pnas.95.6.3168] [PMID: 9501234]
[http://dx.doi.org/10.1038/35036235] [PMID: 11252770]
[http://dx.doi.org/10.1101/cshperspect.a018994] [PMID: 26134318]
[http://dx.doi.org/10.1146/annurev.neuro.28.051804.101459] [PMID: 16022595]
[http://dx.doi.org/10.1002/cne.1040] [PMID: 11406822]
[PMID: 17684532]
[http://dx.doi.org/10.1038/nature09817] [PMID: 21460835]
[http://dx.doi.org/10.1038/s41386-018-0109-6] [PMID: 29941977]
[http://dx.doi.org/10.1038/nn1707] [PMID: 16732202]
[http://dx.doi.org/10.1016/j.tics.2006.10.013] [PMID: 17174137]
[http://dx.doi.org/10.1038/sj.npp.1300358] [PMID: 14702022]
[http://dx.doi.org/10.1186/1756-6606-2-1] [PMID: 19138433]
[http://dx.doi.org/10.1038/nrn.2017.45] [PMID: 28469276]
[http://dx.doi.org/10.1038/nrn2822] [PMID: 20354534]
[http://dx.doi.org/10.1016/S0006-3223(99)00247-4] [PMID: 10599477]
[http://dx.doi.org/10.1523/JNEUROSCI.20-24-09104.2000] [PMID: 11124987]
[http://dx.doi.org/10.1126/science.1083328] [PMID: 12907793]
[http://dx.doi.org/10.1016/j.cell.2007.07.010] [PMID: 17825401]
[http://dx.doi.org/10.1038/nature10287] [PMID: 21814201]
[http://dx.doi.org/10.1016/j.conb.2014.08.012] [PMID: 25240202]
[http://dx.doi.org/10.1101/cshperspect.a021287] [PMID: 25833845]
[http://dx.doi.org/10.1016/S1474-4422(02)00073-X] [PMID: 12849486]
[http://dx.doi.org/10.1523/JNEUROSCI.17-10-03727.1997] [PMID: 9133393]
[http://dx.doi.org/10.1016/S0006-8993(98)00030-4] [PMID: 9593820]
[http://dx.doi.org/10.1016/j.expneurol.2005.08.010] [PMID: 16168988]
[http://dx.doi.org/10.1016/S0304-3940(98)00269-9] [PMID: 9637397]
[http://dx.doi.org/10.1016/S0304-3940(98)00355-3] [PMID: 9654345]
[http://dx.doi.org/10.1016/S0006-3223(00)00228-6] [PMID: 10862803]
[http://dx.doi.org/10.1523/JNEUROSCI.22-08-03174.2002] [PMID: 11943819]
[http://dx.doi.org/10.1002/hipo.1045] [PMID: 11769312]
[http://dx.doi.org/10.1093/jnen/64.3.194] [PMID: 15804050]
[http://dx.doi.org/10.1016/j.nbd.2004.08.008] [PMID: 15571983]
[http://dx.doi.org/10.1523/JNEUROSCI.5516-05.2006] [PMID: 16641251]
[http://dx.doi.org/10.1016/j.stem.2015.04.003] [PMID: 25957904]
[http://dx.doi.org/10.1111/j.1460-9568.2005.04386.x] [PMID: 16262631]
[http://dx.doi.org/10.1016/j.nbd.2003.11.010] [PMID: 15006689]
[http://dx.doi.org/10.1016/j.nbd.2003.08.022] [PMID: 14678767]
[http://dx.doi.org/10.1002/hipo.22752] [PMID: 28608989]
[http://dx.doi.org/10.1159/000114705] [PMID: 1193096]
[http://dx.doi.org/10.1016/j.braindev.2006.08.009] [PMID: 17008043]
[http://dx.doi.org/10.1016/S0014-4886(03)00207-3] [PMID: 14637092]
[http://dx.doi.org/10.1007/s12264-007-0012-3] [PMID: 17592530]
[http://dx.doi.org/10.1111/j.1528-1167.2008.01633.x] [PMID: 18522596]
[http://dx.doi.org/10.1111/j.1460-9568.2011.07612.x] [PMID: 21395857]
[PMID: 26552418]
[http://dx.doi.org/10.1523/JNEUROSCI.5508-05.2006] [PMID: 16611826]
[http://dx.doi.org/10.1002/1096-9861(20001211)428:2<240:AID-CNE4>3.0.CO;2-Q] [PMID: 11064364]
[http://dx.doi.org/10.1016/j.neuroscience.2005.03.059] [PMID: 16344154]
[http://dx.doi.org/10.1523/JNEUROSCI.5655-09.2010] [PMID: 20147533]
[http://dx.doi.org/10.1021/jp0767664] [PMID: 18154286]
[http://dx.doi.org/10.1523/JNEUROSCI.0431-07.2007] [PMID: 17626215]
[http://dx.doi.org/10.1523/JNEUROSCI.2002-07.2007] [PMID: 17728453]
[http://dx.doi.org/10.1002/cne.20182] [PMID: 15269966]
[http://dx.doi.org/10.1016/j.eplepsyres.2005.12.003] [PMID: 16480853]
[http://dx.doi.org/10.1002/ana.20699] [PMID: 16261566]
[http://dx.doi.org/10.1523/JNEUROSCI.20-16-06144.2000] [PMID: 10934264]
[http://dx.doi.org/10.1152/jn.00663.2010] [PMID: 20881195]
[http://dx.doi.org/10.1002/ana.24946] [PMID: 28470680]
[http://dx.doi.org/10.1172/JCI95731] [PMID: 30507615]
[http://dx.doi.org/10.1016/j.neuron.2006.11.004] [PMID: 17178407]
[http://dx.doi.org/10.1111/j.1528-1167.2007.01146.x] [PMID: 17555527]
[PMID: 20865736]
[http://dx.doi.org/10.1016/j.eplepsyres.2017.04.004] [PMID: 28431266]
[http://dx.doi.org/10.1111/j.0953-816X.2004.03412.x] [PMID: 15217378]
[http://dx.doi.org/10.1016/j.nbd.2006.02.016] [PMID: 16806953]
[http://dx.doi.org/10.1016/j.neuron.2012.08.002] [PMID: 22998871]
[http://dx.doi.org/10.1038/ncomms7606] [PMID: 25808087]
[http://dx.doi.org/10.1523/JNEUROSCI.1371-16.2016] [PMID: 27798182]
[http://dx.doi.org/10.1523/JNEUROSCI.0920-19.2019] [PMID: 31308098]
[http://dx.doi.org/10.1016/j.neuron.2016.01.040] [PMID: 26889809]
[http://dx.doi.org/10.1016/j.expneurol.2014.11.009] [PMID: 25476494]
[http://dx.doi.org/10.1016/j.expneurol.2017.04.005] [PMID: 28427858]
[http://dx.doi.org/10.5698/1535-7597.18.4s1.1] [PMID: 30233275]
[http://dx.doi.org/10.1023/A:1018549928277] [PMID: 9368880]
[http://dx.doi.org/10.1016/S0306-4522(98)00041-4] [PMID: 9692746]
[http://dx.doi.org/10.1016/S0304-3940(98)00394-2] [PMID: 9672387]
[http://dx.doi.org/10.1093/med/9780199746545.003.0005]
[http://dx.doi.org/10.1101/cshperspect.a022871] [PMID: 27141079]
[http://dx.doi.org/10.1002/ana.410250610] [PMID: 2545161]
[http://dx.doi.org/10.1007/s12264-017-0134-1] [PMID: 28488083]
[http://dx.doi.org/10.1007/s12264-019-00413-5] [PMID: 31372899]
[http://dx.doi.org/10.1016/0024-3205(96)00492-4] [PMID: 8913326]
[http://dx.doi.org/10.1111/j.1528-1157.2000.tb02163.x] [PMID: 10768292]
[http://dx.doi.org/10.1523/JNEUROSCI.23-18-07069.2003] [PMID: 12904467]
[http://dx.doi.org/10.1007/s11064-012-0897-8] [PMID: 23054073]
[http://dx.doi.org/10.1111/j.1528-1167.2011.03109.x] [PMID: 21635236]
[http://dx.doi.org/10.1007/s12264-017-0097-2] [PMID: 28161868]
[http://dx.doi.org/10.1007/s12264-017-0191-5] [PMID: 29124671]
[http://dx.doi.org/10.1007/s12264-017-0182-6] [PMID: 28936771]
[http://dx.doi.org/10.1111/j.1528-1157.1989.tb05825.x] [PMID: 2548836]
[http://dx.doi.org/10.1016/0920-1211(90)90015-N] [PMID: 1705225]
[PMID: 1939068]
[http://dx.doi.org/10.1038/44579] [PMID: 10548105]
[http://dx.doi.org/10.1016/j.tins.2004.11.011] [PMID: 15667934]
[http://dx.doi.org/10.1007/s12264-018-0273-z] [PMID: 30128691]
[http://dx.doi.org/10.1007/s12264-019-00400-w] [PMID: 31197650]
[http://dx.doi.org/10.1056/NEJM200002033420503] [PMID: 10660394]
[http://dx.doi.org/10.1038/nrd4126] [PMID: 24052047]
[http://dx.doi.org/10.1016/j.yebeh.2017.04.003 ] [PMID: 28551500]
[http://dx.doi.org/10.1016/S1474-4422(12)70153-9] [PMID: 22832500]
[http://dx.doi.org/10.1016/S1474-4422(15)00225-2] [PMID: 26549780]
[http://dx.doi.org/10.1634/stemcells.2007-0177] [PMID: 17673525]
[http://dx.doi.org/10.1523/JNEUROSCI.3206-07.2007] [PMID: 18160639]
[http://dx.doi.org/10.1038/nn.2385] [PMID: 19701197]
[http://dx.doi.org/10.1038/nn.2360] [PMID: 19701198]
[http://dx.doi.org/10.1016/j.cell.2008.12.044] [PMID: 19303846]
[http://dx.doi.org/10.1038/nature04108] [PMID: 16251967]
[http://dx.doi.org/10.1101/gad.975202] [PMID: 11937492]
[http://dx.doi.org/10.1523/JNEUROSCI.23-05-01730.2003] [PMID: 12629177]
[http://dx.doi.org/10.1073/pnas.0710156104] [PMID: 18077357]
[http://dx.doi.org/10.1038/jcbfm.2009.83] [PMID: 19536070]
[http://dx.doi.org/10.1523/JNEUROSCI.4987-09.2010] [PMID: 20203209]
[http://dx.doi.org/10.1038/nn983] [PMID: 12469128]
[http://dx.doi.org/10.1016/S0896-6273(03)00561-0] [PMID: 12971894]
[http://dx.doi.org/10.1038/nn2059] [PMID: 18297065]
[http://dx.doi.org/10.1016/S0896-6273(00)00148-3] [PMID: 11163261]
[http://dx.doi.org/10.1523/JNEUROSCI.3314-07.2008] [PMID: 18784300]
[http://dx.doi.org/10.1523/JNEUROSCI.21-17-06706.2001] [PMID: 11517260]
[http://dx.doi.org/10.1093/jnen/61.10.903] [PMID: 12387456]
[http://dx.doi.org/10.1096/fj.02-0143fje] [PMID: 12154010]
[http://dx.doi.org/10.1046/j.1471-4159.2003.01979.x] [PMID: 12969262]
[http://dx.doi.org/10.1016/j.expneurol.2004.11.016] [PMID: 15755552]
[http://dx.doi.org/10.1073/pnas.182296499] [PMID: 12181492]
[http://dx.doi.org/10.1523/JNEUROSCI.15-06-04687.1995] [PMID: 7790933]
[http://dx.doi.org/10.1523/JNEUROSCI.1999-04.2004] [PMID: 15342728]
[http://dx.doi.org/10.1038/nn1522] [PMID: 16116450]
[http://dx.doi.org/10.1016/S1044-7431(03)00218-5] [PMID: 14664813]
[http://dx.doi.org/10.1073/pnas.2234031100] [PMID: 14581618]
[http://dx.doi.org/10.1126/science.1088417] [PMID: 14615545]
[http://dx.doi.org/10.1016/S0006-3223(03)00700-5] [PMID: 14625142]
[http://dx.doi.org/10.2174/1871527316666170117114513] [PMID: 28124605]
[http://dx.doi.org/10.1002/cbf.3306] [PMID: 29052243]
[http://dx.doi.org/10.1007/s11064-015-1614-1] [PMID: 26012365]
[http://dx.doi.org/10.1016/j.bbrc.2004.05.204] [PMID: 15219872]
[http://dx.doi.org/10.1002/glia.22984] [PMID: 27003605]
[http://dx.doi.org/10.1016/S0169-328X(99)00295-8] [PMID: 10648888]
[http://dx.doi.org/10.1016/j.neuron.2008.06.023] [PMID: 18701066]
[http://dx.doi.org/10.1073/pnas.0803702105] [PMID: 18832146]
[http://dx.doi.org/10.1016/S0166-2236(00)01682-9] [PMID: 11163887]
[http://dx.doi.org/10.1093/med/9780199746545.003.0039]
[http://dx.doi.org/10.1006/exnr.2002.7869] [PMID: 11922662]
[http://dx.doi.org/10.1016/j.nbd.2011.01.001] [PMID: 21220014]
[http://dx.doi.org/10.1016/j.neuron.2013.04.027] [PMID: 23790754]
[http://dx.doi.org/10.1016/j.neuron.2004.06.019] [PMID: 15233915]
[http://dx.doi.org/10.1038/nature05028] [PMID: 16906136]
[http://dx.doi.org/10.1016/j.neuron.2010.03.009] [PMID: 20346761]
[http://dx.doi.org/10.1016/S0028-3908(03)00104-7] [PMID: 12763094]
[http://dx.doi.org/10.1016/j.brainres.2018.09.008] [PMID: 30201259]
[http://dx.doi.org/10.1016/j.neuron.2017.08.013] [PMID: 28858623]
[http://dx.doi.org/10.1038/nature04404] [PMID: 16341203]
[http://dx.doi.org/10.1038/nature11306] [PMID: 22842902]
[http://dx.doi.org/10.1038/nn.3572] [PMID: 24212671]
[http://dx.doi.org/10.1038/nn.3950] [PMID: 25710837]
[http://dx.doi.org/10.1016/j.mcn.2012.01.001] [PMID: 22270046]
[http://dx.doi.org/10.1002/hipo.22192] [PMID: 23966332]
[http://dx.doi.org/10.1523/JNEUROSCI.2723-06.2006] [PMID: 16988041]
[http://dx.doi.org/10.1016/j.bbi.2012.09.003] [PMID: 22985767]
[http://dx.doi.org/10.1016/j.tins.2014.12.006] [PMID: 25579391]
[http://dx.doi.org/10.1016/j.tips.2016.03.001] [PMID: 27062228]
[http://dx.doi.org/10.1517/14740338.2015.1010508] [PMID: 25645535]
[http://dx.doi.org/10.1111/epi.13785] [PMID: 28675559]
[http://dx.doi.org/10.1186/s12974-018-1192-7] [PMID: 29764485]
[http://dx.doi.org/10.1038/nrneurol.2010.178] [PMID: 21135885]
[http://dx.doi.org/10.1038/srep21931] [PMID: 26902320]
[http://dx.doi.org/10.1016/j.expneurol.2016.05.034] [PMID: 27240522]
[http://dx.doi.org/10.1016/j.nbd.2015.07.003] [PMID: 26168875]
[http://dx.doi.org/10.1111/epi.13688] [PMID: 28166388]
[http://dx.doi.org/10.1016/j.nbd.2013.03.006] [PMID: 23523633]
[http://dx.doi.org/10.1016/j.bbi.2017.02.002] [PMID: 28167116]
[http://dx.doi.org/10.1038/nm.2127] [PMID: 20348922]
[http://dx.doi.org/10.1093/brain/awr032] [PMID: 21414994]
[http://dx.doi.org/10.1002/cne.22623] [PMID: 21455997]
[http://dx.doi.org/10.1111/epi.13605] [PMID: 27888509]
[http://dx.doi.org/10.1016/S0306-4522(03)00481-0] [PMID: 14580952]
[http://dx.doi.org/10.1523/JNEUROSCI.5161-12.2013] [PMID: 23699504]
[http://dx.doi.org/10.1126/science.1173215] [PMID: 19590004]
[http://dx.doi.org/10.1016/j.tics.2010.04.003] [PMID: 20471301]
[http://dx.doi.org/10.1038/nn.3260] [PMID: 23143513]
[http://dx.doi.org/10.1016/j.cell.2012.01.046] [PMID: 22365813]
[http://dx.doi.org/10.1016/S1474-4422(04)00906-8] [PMID: 15488459]
[http://dx.doi.org/10.1111/j.1528-1167.2007.01222.x] [PMID: 17662062]
[http://dx.doi.org/10.1016/j.yebeh.2009.02.036] [PMID: 19341977]
[http://dx.doi.org/10.1007/s12264-017-0186-2] [PMID: 29094314]
[http://dx.doi.org/10.1016/j.eplepsyres.2005.09.023] [PMID: 16377148]
[http://dx.doi.org/10.1016/j.yebeh.2007.02.007] [PMID: 17409025]
[http://dx.doi.org/10.1073/pnas.2334169100] [PMID: 14614143]
[http://dx.doi.org/10.1038/386493a0] [PMID: 9087407]
[http://dx.doi.org/10.1038/6368] [PMID: 10195220]
[http://dx.doi.org/10.1523/JNEUROSCI.0110-07.2007] [PMID: 17537967]
[http://dx.doi.org/10.1016/j.neubiorev.2008.10.005] [PMID: 18996146]
[http://dx.doi.org/10.1111/cns.12416] [PMID: 26096304]
[http://dx.doi.org/10.1016/j.nbd.2008.05.007] [PMID: 18632279]
[http://dx.doi.org/10.1186/s12974-018-1063-2] [PMID: 29426321]
[http://dx.doi.org/10.1038/nn1969] [PMID: 17726477]
[http://dx.doi.org/10.1038/s41586-018-0262-4] [PMID: 29950730]
[http://dx.doi.org/10.1016/j.cell.2015.06.034] [PMID: 26186191]
[http://dx.doi.org/10.1111/j.1365-2184.2009.00618.x] [PMID: 19614677]
[http://dx.doi.org/10.1016/j.stemcr.2014.12.002] [PMID: 25556566]
[http://dx.doi.org/10.1016/j.stem.2015.09.002] [PMID: 26526726]