Please wait a minute...
J Zhejiang Univ (Med Sci)  2017, Vol. 46 Issue (1): 15-21    DOI: 10.3785/j.issn.1008-9292.2017.02.03
The role of central cholinergic system in epilepsy
WANG Ying(),WANG Yi,CHEN Zhong()
College of Pharmaceutial Science, Zhejiang University, Hangzhou 310058, China
Download: HTML   HTML( 21 )   PDF(1058KB)
Export: BibTeX | EndNote (RIS)      


Epilepsy is a chronic neurological disorder, which is not only related to the imbalance between excitatory glutamic neurons and inhibitory GABAergic neurons, but also related to abnormal central cholinergic regulation. This article summarizes the scientific background and experimental data about cholinergic dysfunction in epilepsy from both cellular and network levels, further discusses the exact role of cholinergic system in epilepsy. In the cellular level, several types of epilepsy are believed to be associated with aberrant metabotropic muscarinic receptors in several different brain areas, while the mutations of ionotropic nicotinic receptors have been reported to result in a specific type of epilepsy-autosomal dominant nocturnal frontal lobe epilepsy. In the network level, cholinergic projection neurons as well as their interaction with other neurons may regulate the development of epilepsy, especially the cholinergic circuit from basal forebrain to hippocampus, while cholinergic local interneurons have not been reported to be associated with epilepsy. With the development of optogenetics and other techniques, dissect and regulate cholinergic related epilepsy circuit has become a hotspot of epilepsy research.

Key wordsEpilepsy/physiopathology      Receptors, cholinergic      Hippocampus      Neurons      Review     
Received: 02 October 2016      Published: 07 July 2017
CLC:  R741.02  
Corresponding Authors: CHEN Zhong     E-mail:;
About author: CHEN Zhong. E-mail:
Cite this article:

WANG Ying,WANG Yi,CHEN Zhong. The role of central cholinergic system in epilepsy. J Zhejiang Univ (Med Sci), 2017, 46(1): 15-21.

URL:     OR



关键词: 癫痫/病理生理学,  受体, 胆碱能,  海马,  神经元,  综述 
Fig 1 Sites of action for nicotinic and muscarinic acetylcholine receptors
Fig 2 Schematic of cholinergic neurons and networks in the central nervous system
[1]   PITK?NEN A, LUKASIUK K . Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol. 2011, 10(2): 173-186 doi: 10.1016/S1474-4422(10)70310-0
doi: 10.1016/S1474-4422(10)70310-0 pmid: 21256455
[2]   WYKES R C, KULLMANN D M, PAVLOV I et al. Optogenetic approaches to treat epilepsy. J Neurosci Methods. 2016, 260: 215-220 doi: 10.1016/j.jneumeth.2015.06.004
doi: 10.1016/j.jneumeth.2015.06.004 pmid: 26072246
[3]   KROOK-MAGNUSON E, SOLTESZ I . Beyond the hammer and the scalpel:selective circuit control for the epilepsies. Nat Neurosci. 2015, 18(3): 331-338 doi: 10.1038/nn.3943
[4]   KAILA K, RUUSUVUORI E, SEJA P et al. GABA actions and ionic plasticity in epilepsy. Curr Opin Neurobiol. 2014, 26: 34-41
[5]   KHAZIPOV R . GABAergic synchronization in epilepsy. Cold Spring Harb Perspect Med. 2016, 6(2): a022764 doi: 10.1101/cshperspect.a022764
doi: 10.1101/cshperspect.a022764 pmid: 26747834
[6]   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): 692-697 doi: 10.1038/nn.3392
doi: 10.1038/nn.3392
[7]   KROOK-MAGNUSON E, ARMSTRONG C, OIJALA M et al. On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Nat Commun. 2013, 4: 1376 doi: 10.1038/ncomms2376
doi: 10.1038/ncomms2376 pmid: 23340416
[8]   张 力三, 沈 海清, 金 春雷 et al. 脑内组胺对戊四唑慢性癫痫形成过程的作用机制. 浙江大学学报 (医学版). 2004, 33(3): 201-204
ZHANG Lisan, SHEN Haiqing, JIN Chunlei et al. Mechanisms of the effect of brain histamine on chronic epilepsy induced by pentylenetetrazole. Journal of Zhejiang University (Medical Science). 2004, 33(3): 201-204
[9]   CURIA G, LONGO D, BIAGINI G et al. The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods. 2008, 172(2): 143-157 doi: 10.1016/j.jneumeth.2008.04.019
doi: 10.1016/j.jneumeth.2008.04.019 pmid: 2518220
[10]   ELAZAR Z, BERCHANSKI A . Excitatory amino acids modulate epileptogenesis in the brain stem. Neuroreport. 2000, 11(8): 1777-1780 doi: 10.1097/00001756-200006050-00036
doi: 10.1097/00001756-200006050-00036 pmid: 10852243
[11]   FERENCZ I, LEANZA G, NANOBASHVILI A et al. Septal cholinergic neurons suppress seizure development in hippocampal kindling in rats:comparison with noradrenergic neurons. Neuroscience. 2001, 102(4): 819-832 doi: 10.1016/S0306-4522(00)00499-1
doi: 10.1016/S0306-4522(00)00499-1 pmid: 11182245
[12]   HAMILTON S E, LOOSE M D, QI M et al. Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice. Proc Natl Acad Sci U S A. 1997, 94(24): 13311-13316 doi: 10.1073/pnas.94.24.13311
doi: 10.1073/pnas.94.24.13311 pmid: 9371842
[13]   FERINI-STRAMBI L, SANSONI V, COMBI R . Nocturnal frontal lobe epilepsy and the acetylcholine receptor. Neurologist. 2012, 18(6): 343-349 doi: 10.1097/NRL.0b013e31826a99b8
doi: 10.1097/NRL.0b013e31826a99b8 pmid: 23114665
[14]   FRIEDMAN A, BEHRENS C J, HEINEMANN U . Cholinergic dysfunction in temporal lobe epilepsy. Epilepsia. 2007, 48(Suppl 5): 126-130
[15]   PICCIOTTO M R, HIGLEY M J, MINEUR Y S . Acetylcholine as a neuromodulator:cholinergic signaling shapes nervous system function and behavior. Neuron. 2012, 76(1): 116-129 doi: 10.1016/j.neuron.2012.08.036
doi: 10.1016/j.neuron.2012.08.036 pmid: 3466476
[16]   ITO H T, SCHUMAN E M . Frequency-dependent signal transmission and modulation by neuromodulators. Front Neurosci. 2008, 2(2): 138-144 doi: 10.3389/neuro.01.027.2008
doi: 10.3389/neuro.01.027.2008 pmid: 2622745
[17]   WESS J . Novel insights into muscarinic acetylcholine receptor function using gene targeting technology. Trends Pharmacol Sci. 2003, 24(8): 414-420 doi: 10.1016/S0165-6147(03)00195-0
doi: 10.1016/S0165-6147(03)00195-0 pmid: 12915051
[18]   WESS J, DUTTAROY A, ZHANG W et al. M1-M5 muscarinic receptor knockout mice as novel tools to study the physiological roles of the muscarinic cholinergic system. Receptors Channels. 2003, 9(4): 279-290 doi: 10.1080/10606820308262
doi: 10.1023/A:1022844517200 pmid: 12893539
[19]   POTIER S, PSARROPOULOU C . Endogenous acetylcholine facilitates epileptogenesis in immature rat neocortex. Neurosci Lett. 2001, 302(1): 25-28 doi: 10.1016/S0304-3940(01)01641-X
doi: 10.1016/S0304-3940(01)01641-X pmid: 11278103
[20]   BAGRI A, DI S G, SANDNER G . Myoclonic and tonic seizures elicited by microinjection of cholinergic drugs into the inferior colliculus. Therapie. 1999, 54(5): 589-594
[21]   BYMASTER F P, CARTER P A, YAMADA M et al. Role of specific muscarinic receptor subtypes in cholinergic parasympathomimetic responses, in vivo phosphoinositide hydrolysis, and pilocarpine-induced seizure activity. Eur J Neurosci. 2003, 17(7): 1403-1410 doi: 10.1046/j.1460-9568.2003.02588.x
[22]   KAWAI H, LAZAR R, METHERATE R . Nicotinic control of axon excitability regulates thalamocortical transmission. Nat Neurosci. 2007, 10(9): 1168-1175 doi: 10.1038/nn1956
doi: 10.1038/nn1956 pmid: 17704774
[23]   RAGGENBASS M, BERTRAND D . Nicotinic receptors in circuit excitability and epilepsy. J Neurobiol. 2002, 53(4): 580-589 doi: 10.1002/(ISSN)1097-4695
doi: 10.1002/neu.10152 pmid: 12436422
[24]   BUCHER D, GOAILLARD J M . Beyond faithful conduction:short-term dynamics, neuromodulation, and long-term regulation of spike propagation in the axon. Prog Neurobiol. 2011, 94(4): 307-346 doi: 10.1016/j.pneurobio.2011.06.001
doi: 10.1016/j.pneurobio.2011.06.001 pmid: 21708220
[25]   YAKEL J L . Nicotinic ACh receptors in the hippocampus:role in excitability and plasticity. Nicotine Tob Res. 2012, 14(11): 1249-1257 doi: 10.1093/ntr/nts091
doi: 10.1093/ntr/nts091 pmid: 22472168
[26]   WOOLF A, BURKHART K, CARACCIO T et al. Self-poisoning among adults using multiple transdermal nicotine patches. J Toxicol Clin Toxicol. 1996, 34(6): 691-698 doi: 10.3109/15563659609013830
doi: 10.3109/15563659609013830 pmid: 8941198
[27]   BECCHETTI A, ARACRI P, MENEGHINI S et al. The role of nicotinic acetylcholine receptors in autosomal dominant nocturnal frontal lobe epilepsy. Front Physiol. 2015, 6: 22
doi: 10.3389/fphys.2015.00022 pmid: 25717303
[28]   WANG M Y, LIU X Z, WANG J et al. A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in a Chinese patient with non-familial nocturnal frontal lobe epilepsy. Epilepsy Res. 2014, 108(10): 1927-1931 doi: 10.1016/j.eplepsyres.2014.08.024
doi: 10.1016/j.eplepsyres.2014.08.024 pmid: 25282705
[29]   SALAS R, COOK K D, BASSETTO L et al. The alpha3 and beta4 nicotinic acetylcholine receptor subunits are necessary for nicotine-induced seizures and hypolocomotion in mice. Neuropharmacology. 2004, 47(3): 401-407 doi: 10.1016/j.neuropharm.2004.05.002
doi: 10.1016/j.neuropharm.2004.08.005 pmid: 15275829
[30]   PAZ J T, HUGUENARD J R . Microcircuits and their interactions in epilepsy:is the focus out of focus?. Nat Neurosci. 2015, 18(3): 351-359 doi: 10.1038/nn.3950
doi: 10.1038/nn.3950 pmid: 25710837
[31]   GOLDBERG E M, COULTER D A . Mechanisms of epileptogenesis:a convergence on neural circuit dysfunction. Nat Rev Neurosci. 2013, 14(5): 337-349 doi: 10.1038/nrn3482
doi: 10.1038/nrn3482 pmid: 23595016
[32]   刘 扬, 汪 仪, 许 正浩 et al. 低频率电刺激抑制杏仁核电点燃癫痫刺激模式依赖效应的实验研究. 浙江大学学报 (医学版). 2015, 44(5): 539-545
LIU Yang, WANG Yi, XU Zhenghao et al. Antiepileptic effect of low frequency stimulation in kindling rats. Journal of Zhejiang University (Medical Science). 2015, 44(5): 539-545
[33]   陶 安风, 许 正浩, 吴 承昊 et al. 不同波形低频率电刺激对小鼠海马电点燃癫痫的作用比较. 浙江大学学报 (医学版). 2015, 44(3): 315-322
TAO Anfeng, XU Zhenghao, WU Chenghao et al. Antiepileptic effect of low-frequency electrical stimulation is waveform-dependent in hippocampal kindled mice. Journal of Zhejiang University (Medical Science). 2015, 44(3): 315-322
[34]   ASTON-JONES G, DEISSEROTH K . Recent advances in optogenetics and pharmacogenetics. Brain Res. 2013, 1511: 1-5 doi: 10.1016/j.brainres.2013.01.026
doi: 10.1016/j.brainres.2013.01.026 pmid: 3663045
[35]   TYE K M, DEISSEROTH K . Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat Rev Neurosci. 2012, 13(4): 251-266 doi: 10.1038/nrn3171
doi: 10.1038/nrn3171
[36]   PAZ J T, DAVIDSON T J, FRECHETTE E S et al. Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury. Nat Neurosci. 2013, 16(1): 64-70
[37]   LIN S C, BROWN R E, HUSSAIN SHULERM G et al. Optogenetic dissection of the basal forebrain neuromodulatory control of cortical activation, plasticity, and cognition. J Neurosci. 2015, 35(41): 13896-13903 doi: 10.1523/JNEUROSCI.2590-15.2015
doi: 10.1523/JNEUROSCI.2590-15.2015 pmid: 26468190
[38]   CHEN N, SUGIHARA H, SUR M . An acetylcholine-activated microcircuit drives temporal dynamics of cortical activity. Nat Neurosci. 2015, 18(6): 892-902 doi: 10.1038/nn.4002
doi: 10.1038/nn.4002 pmid: 25915477
[39]   BELL L A, BELL K A, MCQUISTON A R . Acetylcholine release in mouse hippocampal CA1 preferentially activates inhibitory-selective interneurons via α4β2* nicotinic receptor activation. Front Cell Neurosci. 2015, 9: 115
[40]   VANDECASTEELE M, VARGA V, BERéNYI A et al. Optogenetic activation of septal cholinergic neurons suppresses sharp wave ripples and enhances theta oscillations in the hippocampus. Proc Natl Acad Sci U S A. 2014, 111(37): 13535-13540 doi: 10.1073/pnas.1411233111
doi: 10.1073/pnas.1411233111 pmid: 25197052
[41]   GARCíA-HERNáNDEZ A, BLAND B H, FACELLI J C et al. Septo-hippocampal networks in chronic epilepsy. Exp Neurol. 2010, 222(1): 86-92 doi: 10.1016/j.expneurol.2009.12.010
doi: 10.1016/j.expneurol.2009.12.010 pmid: 20026111
[42]   SUN Y, NGUYEN A Q, NGUYEN J P et al. Cell-type-specific circuit connectivity of hippocampal CA1 revealed through Cre-dependent rabies tracing. Cell Rep. 2014, 7(1): 269-280 doi: 10.1016/j.celrep.2014.02.030
doi: 10.1016/j.celrep.2014.02.030 pmid: 24656815
[43]   DANNENBERG H, PABST M, BRAGANZA O et al. Synergy of direct and indirect cholinergic septo-hippocampal pathways coordinates firing in hippocampal networks. J Neurosci. 2015, 35(22): 8394-8410 doi: 10.1523/JNEUROSCI.4460-14.2015
doi: 10.1523/JNEUROSCI.4460-14.2015 pmid: 26041909
[44]   CHAUVIèRE L, RAFRAFI N, THINUS-BLANC C et al. Early deficits in spatial memory and theta rhythm in experimental temporal lobe epilepsy. J Neurosci. 2009, 29(17): 5402-5410 doi: 10.1523/JNEUROSCI.4699-08.2009
doi: 10.1523/JNEUROSCI.4699-08.2009 pmid: 19403808
[45]   COLOM L V, GARCíA-HERNáNDEZ A, CASTA?EDA M T et al. Septo-hippocampal networks in chronically epileptic rats:potential antiepileptic effects of theta rhythm generation. J Neurophysiol. 2006, 95(6): 3645-3653 doi: 10.1152/jn.00040.2006
doi: 10.1152/jn.00040.2006 pmid: 16554504
[46]   KITCHIGINA V F, BUTUZOVA M V . Theta activity of septal neurons during different epileptic phases:the same frequency but different significance?. Exp Neurol. 2009, 216(2): 449-458 doi: 10.1016/j.expneurol.2009.01.001
doi: 10.1533/wint.2005.3445 pmid: 19168062
[47]   KUNDISHORA A J, GUMMADAVELLI A, MA C et al. Restoring conscious arousal during focal limbic seizures with deep brain stimulation. Cereb Cortex. 2016 pii:bhw035 doi: 10.1093/cercor/bhw035
doi: 10.1093/cercor/bhw035 pmid: 26941379
[48]   MOTELOW J E, LI W, ZHAN Q, et al. Decreased subcortical cholinergic arousal in focal seizures. Neuron. 2015, 85(3): 561-572 doi: 10.1016/j.neuron.2014.12.058
doi: 10.1016/j.neuron.2014.12.058 pmid: 25654258
[1] FENG Mengyu, ZHANG Taiping, ZHAO Yupei. Present situation and prospect of enhanced recovery after surgery in pancreatic surgery[J]. J Zhejiang Univ (Med Sci), 2017, 46(6): 666-674.
[2] XU Jingjing, TAN Yanbin, ZHANG Minming. Medical imaging in tumor precision medicine: opportunities and challenges[J]. J Zhejiang Univ (Med Sci), 2017, 46(5): 455-461.
[3] PAN Jingying, HE Mengye, KE Wei, HU Menglin, WANG Meifang, SHEN Peng. Advances on correlation of PET-CT findings with breast cancer molecular subtypes, treatment response and prognosis[J]. J Zhejiang Univ (Med Sci), 2017, 46(5): 473-480.
[4] ZHANG Siying, CHEN Feng. Research progress of CT/MRI parametric response map in precision evaluation of therapeutic response of cancer patients[J]. J Zhejiang Univ (Med Sci), 2017, 46(5): 468-472.
[5] PAN Yao, CHEN Jieyu, YU Risheng. Accurate imaging diagnosis and evaluation of pancreatic cancer[J]. J Zhejiang Univ (Med Sci), 2017, 46(5): 462-467.
[6] WANG Mengyan, ZHU Biao. Research progress on genes mutations related to sulfa drug resistance in Pneumocystis jirovecii[J]. J Zhejiang Univ (Med Sci), 2017, 46(5): 563-569.
[7] LI Yandie, LU Meiping. Progress on the study of NLRP3 inflammasome in autoinflammatory diseases of children[J]. J Zhejiang Univ (Med Sci), 2017, 46(4): 449-453.
[8] WANG Liya, QIAN Yeqing, JIN Fan. Research progress on the safety of offsprings conceived by assisted reproductive technology[J]. J Zhejiang Univ (Med Sci), 2017, 46(3): 279-284.
[9] YAN Kai, JIN Fan. Advances on prenatal diagnosis of birth defects associated with genetic disorders[J]. J Zhejiang Univ (Med Sci), 2017, 46(3): 227-232.
[10] TANG Minyue, ZHU Yimin. The involvement of galectin-1 in implantation and pregnancy maintenance at the maternal-fetal interface[J]. J Zhejiang Univ (Med Sci), 2017, 46(3): 321-327.
[11] FU Xiaohua, XU Weihai, QIU Shengchun, SHU Jing. Research progress on the relationship of brown adipose tissue with polycystic ovary syndrome[J]. J Zhejiang Univ (Med Sci), 2017, 46(3): 315-320.
[12] FU Yanling, ZHU Yimin. Potential clinical application of Kisspeptin in reproductive endocrinology[J]. J Zhejiang Univ (Med Sci), 2017, 46(3): 328-333.
[13] QIAN Yeqing, WANG Liya, LUO Yuqin, YAN Kai, DONG Minyue, JIN Fan. Advances in the application of high-throughput sequencing in clinical genetics[J]. J Zhejiang Univ (Med Sci), 2017, 46(3): 334-337.
[14] SHEN Dan, WANG Fangfang, JIANG Zhou, QU Fan. Long-term effects of polycystic ovary syndrome on the offspring[J]. J Zhejiang Univ (Med Sci), 2017, 46(3): 300-304.
[15] HE Yujie,PAN Jianping. Progress on mechanisms for pathogensto evade NOD-like receptor and Toll-like receptor signaling pathways[J]. J Zhejiang Univ (Med Sci), 2017, 46(2): 218-224.