神经调节蛋白 1/erb-b2 受体酪氨酸激酶 4 与癫痫相关性及其遗传易感性研究进展_Journal of Epilepsy

Authors：

陈新元 , 武羽洁 , 季雨伟 ,  唐薇

昆明医科大学第一附属医院科教科（昆明 650032）;

Corresponding author：

唐薇, Email: tangw666@sina.com

Keywords：

癫痫; 神经调节蛋白 1; erb-b2 受体酪氨酸激酶 4

DOI：

10.7507/2096-0247.20200008

Video：

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癫痫是一种病因复杂、反复发作的神经系统疾病，其发作难以预测，约 1/3 的患者经过抗癫痫治疗无效发展成为药物难治性癫痫。神经调节蛋白 1 (Neuregulin 1, NRG1) 是一种内源性生长因子，erb-b2 受体酪氨酸激酶 4 (erb-b2 receptor tyrosine kinase 4, ErbB4) 是其重要受体。NRG1 和 ErbB4 都与神经发育、神经传递和突触可塑性有关。而遗传因素作为内因，在癫痫的发病机制中起到非常重要的作用，因此 NRG1 和/或 ErbB4 基因突变可能增加癫痫易感性和加剧癫痫进程。既往研究在 NRG1 和 ErbB4 功能以及基因多态性可能导致癫痫风险增加的生物学基础方面取得了令人振奋的进展，文章就相关研究作一综述，以期为 NRG1/ErbB4 与癫痫相关基础研究提供方向。

Citation： 陈新元, 武羽洁, 季雨伟, 唐薇. 神经调节蛋白 1/erb-b2 受体酪氨酸激酶 4 与癫痫相关性及其遗传易感性研究进展. Journal of Epilepsy, 2020, 6(1): 39-43. doi: 10.7507/2096-0247.20200008 Copy

1.	唐颖莹, 陆璐, 周东. 中国癫痫诊断治疗现状. 癫痫杂志, 2019, 5(3): 161-164.
2.	Robert f, Cross h, Jacqueline a, et al. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 522-530.
3.	Gbd 2016 Healthcare Access And Quality Collaborators. Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: a systematic analysis from the Global Burden of Disease Study 2016. Lancet, 2018, 391(10136): 2236-2271.
4.	Scheffer I, Berkovic S, Capovilla G, Mary B, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 512-521.
5.	Stéphane A, Roberta Cilio M, Annamaria V. Current understanding and neurobiology of epileptic encephalopathies. Neurobiology of Disease, 2016, 92(3): 72-89.
6.	Pedro A, Ivette B-C, Niina L, et al. Acute non-convulsive status epilepticus after experimental traumatic brain injury in rats. Journal of neurotrauma, 2018, 36(11): 1890-1907.
7.	Chuang SH, Reddy DS. Genetic and molecular regulation of extrasynaptic GABA-A receptors in the brain: Therapeutic insights for epilepsy. The Journal of Pharmacology and Experimental Therapeutics, 2018, 364(2): 180-179.
8.	Lin M, Klaus-Armin N. Neuregulin-ERBB Signaling in the nervous system and neuropsychiatric diseases. Neuron, 2014, 83(1): 27-49.
9.	Mei L, Xiong WC. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci, 2008, 9(6): 437-452.
10.	Barnes A, Isohanni M, Barnett JH, et al. Neuregulin-1 genotype is associated with structural differences in the normal human brain. Neuroimage, 2012, 59(3): 2057-2061.
11.	Yang CP, Wang HA, Tsai TH, et al. Characterization of the neuropsychological phenotype of glycine N-methyltransferase-/- mice and evaluation of its responses to clozapine and sarcosine treatments. European Neuropsychopharmacology, 2012, 22(8): 596-606.
12.	Jörg Neddens, Kenneth N, Ludovic Tricoire, et al. Conserved interneuron-specific ErbB4 expression in frontal cortex of rodents, monkeys, and humans: implications for schizophrenia. Biological Psychiatry, 2011, 70(7): 636-654.
13.	Papa M, Boscia F, Canitano A, et al. Expression pattern of the ether-a-gogo-related (ERG) K+ channel-encoding genes ERG1, ERG2, and ERG3 in the adult rat central nervous system. The Journal of Comparative Neurology, 2003, 466(1): 119-135.
14.	Dziedzic B, Prevot V, Lomniczi A, et al. Neuron-to-glia signaling mediated by excitatory amino acid receptors regulates ErbB receptor function in astroglial cells of the neuroendocrine brain. The Journal of Neuroscience, 2003, 23(3): 915-926.
15.	Tidcombe H, Jackson-Fisher A, Mathers K, et al. Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality. Proc Natl Acad Sci U S A, 2003, 100(14): 8281-8286.
16.	Fornasari BE, El Soury M, De Marchis S, et al. Neuregulin1 alpha activates migration of neuronal progenitors expressing ErbB4. Molecular and Cellular Neuroscience, 2016, 77(6): 87-94.
17.	Bernd F, Elliott Karen L, Gabriela P, et al. Neuronal migration generates new populations of neurons that develop unique connections, physiological properties and pathologies. Frontiers in cell and developmental biology, 2019, 7: 59.
18.	Guillermina López-Bendito, Aline Cautinat, Juan Antonio Sánchez, et al. Tangential neuronal migration controls axon guidance: a role for neuregulin-1 in thalamocortical axon navigation. Cell, 2006, 125(1): 142.
19.	Hardeep K, Arsalan A, Soheila KA. Neuregulin-1/ErbB network: an emerging modulator of nervous system injury and repair. Progress in Neurobiology, 2019: 101643.
20.	Li B, Woo RS, Mei L, et al. The neuregulin-1 receptor ErbB4 controls glutamatergic synapse maturation and plasticity. Neuron, 2007, 54(4): 583-597.
21.	Wen L, Lu YS, Zhu XH, et al. Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proceedings of the National Academy of Sciences of the United States of America, 2010, 107(3): 1211-1216.
22.	Auger ML, Meccia J, Galea LAM, et al. Disinhibition of the prefrontal cortex leads to brain-wide increases in neuronal activation that are modified by spatial learning. Brain Struct Funct, 2019, 224(1): 171-190.
23.	Chang Q, Fischbach GD. An acute effect of neuregulin 1 beta to suppress alpha 7-containing nicotinic acetylcholine receptors in hippocampal interneurons. J Neurosci, 2006, 26(44): 11295-11303.
24.	Mann MA, Das S, Zhang J, et al. Neuregulin effect on quantal content dissociated from effect on miniature endplate potential amplitude. J Neurophysiol, 2006, 96(2): 671-676.
25.	Zhu JM, Li KX, Cao SX, et al. Increased NRG1-ErbB4 signaling in human symptomatic epilepsy. Scientific reports, 2017, 7(1): 141.
26.	Li KX, Lu YM, Xu ZH, et al. Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy. Nat Neurosci, 2011, 15(2): 267-273.
27.	Ma T, Wu Y, Chen B, et al. D-serine contributes to seizure development via ERK signaling. Front Neurosci, 2019, 13(4): 254.
28.	Tan GH, Liu YY, Hu XL, et al. Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons. Nat Neurosci, 2011, 15(2): 258-266.
29.	Woo RS, Li XM, Tao Y, et al. Neuregulin-1 enhances depolarization-induced GABA release. Neuron, 2007, 54(4): 599-610.
30.	Alese OO, Mabandla MV. Upregulation of hippocampal synaptophysin, GFAP and mGluR3 in a pilocarpine rat model of epilepsy with history of prolonged febrile seizure. J Chem Neuroanat, 2019, 100: 101659.
31.	Nateri AS, Raivich G, Gebhardt C, et al. ERK activation causes epilepsy by stimulating NMDA receptor activity. EMBO J, 2007, 26(23): 4891-4901.
32.	Chen YJ, Zhang M, Yin DM, et al. ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation. Proc Natl Acad Sci USA, 2010, 107(50): 21818-21823.
33.	Deng C, Pan B, Engel M, et al. Neuregulin-1 signalling and antipsychotic treatment: potential therapeutic targets in a schizophrenia candidate signalling pathway. Psychopharmacology, 2013, 226(2): 201-215.
34.	Cascella NG, Schretlen DJ, Sawa A. Schizophrenia and epilepsy: is there a shared susceptibility? Neurosci Res, 2009, 63(4): 227-235.
35.	Bob P, Palus M, Susta M, et al. Sensitization, epilepticlike symptoms and local synchronization in patients with paranoid schizophrenia. Prog Neuro-psychoph, 2010, 34(1): 143-146.
36.	Qin P, Xu H, Laursen TM, et al. Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: population based cohort study. BMJ, 2005, 331(7507): 23.
37.	Dedeurwaerdere S, Boets S, Janssens P, et al. In the greyzone between epilepsy and schizophrenia: alterations in group Ⅱ metabotropic glutamate receptors. Acta Neurol Belg, 2015, 115(3): 221-232.
38.	Zhu WY, Jiang P, He X, et al. Contribution of NRG1 gene polymorphisms in temporal lobe epilepsy. Journal of Child Neurology, 2016, 31(3): 271-276.
39.	Backx L, Ceulemans B, Vermeesch JR, et al. Early myoclonic encephalopathy caused by a disruption of the neuregulin-1 receptor ErbB4. Eur J Hum Genet, 2009, 17(3): 378-382.
40.	Fisahn A, Neddens J, Yan L, et al. Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia. Cereb Cortex, 2009, 19(3): 612-618.

1. 唐颖莹, 陆璐, 周东. 中国癫痫诊断治疗现状. 癫痫杂志, 2019, 5(3): 161-164.
2. Robert f, Cross h, Jacqueline a, et al. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 522-530.
3. Gbd 2016 Healthcare Access And Quality Collaborators. Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: a systematic analysis from the Global Burden of Disease Study 2016. Lancet, 2018, 391(10136): 2236-2271.
4. Scheffer I, Berkovic S, Capovilla G, Mary B, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 512-521.
5. Stéphane A, Roberta Cilio M, Annamaria V. Current understanding and neurobiology of epileptic encephalopathies. Neurobiology of Disease, 2016, 92(3): 72-89.
6. Pedro A, Ivette B-C, Niina L, et al. Acute non-convulsive status epilepticus after experimental traumatic brain injury in rats. Journal of neurotrauma, 2018, 36(11): 1890-1907.
7. Chuang SH, Reddy DS. Genetic and molecular regulation of extrasynaptic GABA-A receptors in the brain: Therapeutic insights for epilepsy. The Journal of Pharmacology and Experimental Therapeutics, 2018, 364(2): 180-179.
8. Lin M, Klaus-Armin N. Neuregulin-ERBB Signaling in the nervous system and neuropsychiatric diseases. Neuron, 2014, 83(1): 27-49.
9. Mei L, Xiong WC. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci, 2008, 9(6): 437-452.
10. Barnes A, Isohanni M, Barnett JH, et al. Neuregulin-1 genotype is associated with structural differences in the normal human brain. Neuroimage, 2012, 59(3): 2057-2061.
11. Yang CP, Wang HA, Tsai TH, et al. Characterization of the neuropsychological phenotype of glycine N-methyltransferase-/- mice and evaluation of its responses to clozapine and sarcosine treatments. European Neuropsychopharmacology, 2012, 22(8): 596-606.
12. Jörg Neddens, Kenneth N, Ludovic Tricoire, et al. Conserved interneuron-specific ErbB4 expression in frontal cortex of rodents, monkeys, and humans: implications for schizophrenia. Biological Psychiatry, 2011, 70(7): 636-654.
13. Papa M, Boscia F, Canitano A, et al. Expression pattern of the ether-a-gogo-related (ERG) K+ channel-encoding genes ERG1, ERG2, and ERG3 in the adult rat central nervous system. The Journal of Comparative Neurology, 2003, 466(1): 119-135.
14. Dziedzic B, Prevot V, Lomniczi A, et al. Neuron-to-glia signaling mediated by excitatory amino acid receptors regulates ErbB receptor function in astroglial cells of the neuroendocrine brain. The Journal of Neuroscience, 2003, 23(3): 915-926.
15. Tidcombe H, Jackson-Fisher A, Mathers K, et al. Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality. Proc Natl Acad Sci U S A, 2003, 100(14): 8281-8286.
16. Fornasari BE, El Soury M, De Marchis S, et al. Neuregulin1 alpha activates migration of neuronal progenitors expressing ErbB4. Molecular and Cellular Neuroscience, 2016, 77(6): 87-94.
17. Bernd F, Elliott Karen L, Gabriela P, et al. Neuronal migration generates new populations of neurons that develop unique connections, physiological properties and pathologies. Frontiers in cell and developmental biology, 2019, 7: 59.
18. Guillermina López-Bendito, Aline Cautinat, Juan Antonio Sánchez, et al. Tangential neuronal migration controls axon guidance: a role for neuregulin-1 in thalamocortical axon navigation. Cell, 2006, 125(1): 142.
19. Hardeep K, Arsalan A, Soheila KA. Neuregulin-1/ErbB network: an emerging modulator of nervous system injury and repair. Progress in Neurobiology, 2019: 101643.
20. Li B, Woo RS, Mei L, et al. The neuregulin-1 receptor ErbB4 controls glutamatergic synapse maturation and plasticity. Neuron, 2007, 54(4): 583-597.
21. Wen L, Lu YS, Zhu XH, et al. Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proceedings of the National Academy of Sciences of the United States of America, 2010, 107(3): 1211-1216.
22. Auger ML, Meccia J, Galea LAM, et al. Disinhibition of the prefrontal cortex leads to brain-wide increases in neuronal activation that are modified by spatial learning. Brain Struct Funct, 2019, 224(1): 171-190.
23. Chang Q, Fischbach GD. An acute effect of neuregulin 1 beta to suppress alpha 7-containing nicotinic acetylcholine receptors in hippocampal interneurons. J Neurosci, 2006, 26(44): 11295-11303.
24. Mann MA, Das S, Zhang J, et al. Neuregulin effect on quantal content dissociated from effect on miniature endplate potential amplitude. J Neurophysiol, 2006, 96(2): 671-676.
25. Zhu JM, Li KX, Cao SX, et al. Increased NRG1-ErbB4 signaling in human symptomatic epilepsy. Scientific reports, 2017, 7(1): 141.
26. Li KX, Lu YM, Xu ZH, et al. Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy. Nat Neurosci, 2011, 15(2): 267-273.
27. Ma T, Wu Y, Chen B, et al. D-serine contributes to seizure development via ERK signaling. Front Neurosci, 2019, 13(4): 254.
28. Tan GH, Liu YY, Hu XL, et al. Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons. Nat Neurosci, 2011, 15(2): 258-266.
29. Woo RS, Li XM, Tao Y, et al. Neuregulin-1 enhances depolarization-induced GABA release. Neuron, 2007, 54(4): 599-610.
30. Alese OO, Mabandla MV. Upregulation of hippocampal synaptophysin, GFAP and mGluR3 in a pilocarpine rat model of epilepsy with history of prolonged febrile seizure. J Chem Neuroanat, 2019, 100: 101659.
31. Nateri AS, Raivich G, Gebhardt C, et al. ERK activation causes epilepsy by stimulating NMDA receptor activity. EMBO J, 2007, 26(23): 4891-4901.
32. Chen YJ, Zhang M, Yin DM, et al. ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation. Proc Natl Acad Sci USA, 2010, 107(50): 21818-21823.
33. Deng C, Pan B, Engel M, et al. Neuregulin-1 signalling and antipsychotic treatment: potential therapeutic targets in a schizophrenia candidate signalling pathway. Psychopharmacology, 2013, 226(2): 201-215.
34. Cascella NG, Schretlen DJ, Sawa A. Schizophrenia and epilepsy: is there a shared susceptibility? Neurosci Res, 2009, 63(4): 227-235.
35. Bob P, Palus M, Susta M, et al. Sensitization, epilepticlike symptoms and local synchronization in patients with paranoid schizophrenia. Prog Neuro-psychoph, 2010, 34(1): 143-146.
36. Qin P, Xu H, Laursen TM, et al. Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: population based cohort study. BMJ, 2005, 331(7507): 23.
37. Dedeurwaerdere S, Boets S, Janssens P, et al. In the greyzone between epilepsy and schizophrenia: alterations in group Ⅱ metabotropic glutamate receptors. Acta Neurol Belg, 2015, 115(3): 221-232.
38. Zhu WY, Jiang P, He X, et al. Contribution of NRG1 gene polymorphisms in temporal lobe epilepsy. Journal of Child Neurology, 2016, 31(3): 271-276.
39. Backx L, Ceulemans B, Vermeesch JR, et al. Early myoclonic encephalopathy caused by a disruption of the neuregulin-1 receptor ErbB4. Eur J Hum Genet, 2009, 17(3): 378-382.
40. Fisahn A, Neddens J, Yan L, et al. Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia. Cereb Cortex, 2009, 19(3): 612-618.

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