星形胶质细胞对兴奋性氨基酸神经递质的调控及与癫痫的关系

摘要/Abstract

摘要： 星形胶质细胞是中枢神经系统中最为丰富的细胞类型，其主要生理功能之一是调控中枢神经递质的稳态，从而在维持中枢神经兴奋性和抑制性平衡中扮演着关键性的角色。星形胶质细胞这种功能对调控胞外兴奋性神经递质谷氨酸和抑制性神经递质γ-氨基丁酸（γ-aminobutyric acid，GABA）尤为突出，即星形胶质细胞可通过谷氨酸-谷氨酰胺-GABA循环对正常状态下抑制性和兴奋性神经递质的循环利用具有重要意义，此外对避免因胞外谷氨酸蓄积造成的兴奋性毒性同样不可或缺。星形胶质细胞功能紊乱如谷氨酸转运体、谷氨酰胺合成酶、谷氨酸脱氢酶的减少可损伤或削弱星形胶质细胞调控神经递质的功能，可表现为胞外谷氨酸水平升高同时伴有GABA水平降低，这种病理改变与癫痫的发生发展密切相关。本文就星形胶质细胞对神经递质的调控及与癫痫的关系进行综述。

关键词: 星形胶质细胞, 谷氨酸, 癫痫

Abstract: Astrocytes are the most abundant cell type in central nervous system, exerting essential physiological functions to keep balance between the excitatory and inhibitory neurotransmitter levels, especially in the regulation of glutamate and GABA. Astrocytes could preserve cells from the potential toxicity caused by the glutamate accumulation through the glutamine-glutamate-GABA cycle; besides, the cycle between excitatory and inhibitory neurotransmitters is of great significance under normal condition. Dysfunction of astrocytes, such as a decrease in glutamate transporters, glutamine synthetase or glutamate dehydrogenase, is closely related to occurrence and development of epilepsy. This paper mainly reviews the research progression in how astrocytes regulate neurotransmitters and the causative role of astrocyte dysfunction in epilepsy.

Key words: astrocytes, glutamate, epilepsy

凌鹏，李月月，钱恒，连晓媛. 星形胶质细胞对兴奋性氨基酸神经递质的调控及与癫痫的关系[J]. 神经药理学报, 2015, 5(2): 46-53.

LING Peng，LI Yue-yue，QIAN Heng，LIAN Xiao-yuan. Regulation of Excitatory Amino Acid Neurotransmitter by Astrocytes and Its Impact to Epilepsy[J]. Acta Neuropharmacologica, 2015, 5(2): 46-53.

参考文献

[1] Arne Schousboe, Lasse Kristoffer Bak, Karsten Kirkegaard Madsen, et al. Amino acid neurotransmitter synthesis and removal[M]. Neuroglia. Oxford University Press, Oxford, UK, 2012: 443-456.

[2] Lajtha A, Berl S, Waelsch H. Amino acid and protein metabolism of the brain—IV[J]. J Neurochemistry, 1959, 3(4): 322-332.

[3] Amina A Qutub, C Anthony Hunt. Glucose transport to the brain: a systems model[J]. Brain Res Rev, 2005, 49(3):595–617.

[4] Mireille Bélanger, Igor Allaman, Pierre J Magistretti. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation[J]. Cell Metab, 2011, 14(6): 724-738.

[5] Lomako J, Lomako W M, Whelan W J, et al. Glycogen synthesis in the astrocyte: from glycogenin to proglycogen to glycogen[J]. J FASEB, 1993, 7(14): 1386-1393.

[6] Bourasb C, Martinc J L, Stellac N, et al. Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle[J]. Dev Neurosci, 1998, 20(4-5): 291-299.

[7] Luc Pellerin, Andrew P Halestrap, Karin Pierre. Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain[J]. J Neurosci Res, 2005, 79(1-2): 55-64.

[8] Harold K Kimelberg, Eric Rutledge, Susan Goderie, et al. Astrocytic swelling due to hypotonic or high K+ medium causes inhibition of glutamate and aspartate uptake and increases their release[J]. J Cereb Blood Flow Metab, 1995, 15(3): 409-416.

[9] Edgar L Perez, Fredrik Lauritzen, Wang Yue, et al. Evidence for astrocytes as a potential source of the glutamate excess in temporal lobe epilepsy[J]. Neurobiology Disease, 2012, 47(3): 331-337.

[10] Mirko Santello, Paola Bezzi, Andrea Volterra. TNFα controls glutamatergic gliotransmission in the hippocampal dentate gyrus[J]. Neuron, 2011, 69(5): 988-1001.

[11] Alfonso Araque, Li Nian-zhen, Robert T Doyle, et al. SNARE protein-dependent glutamate release from astrocytes[J]. J Neurosci, 2000, 20(2): 666-673.

[12] Paola Bezzi, Giorgio Carmignoto, Lucia Pasti, et al. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes[J]. Nature, 1998, 391(6664): 281-285.

[13] Vladimir Parpura, Trent A Basarsky, Liu Fang, et al. Glutamate-mediated astrocyte–neuron signalling[J]. Nature, 1994, 369:744–747.

[14] Nicola B Hamilton, David Attwell. Do astrocytes really exocytose neurotransmitters?[J]. Nat Rev Neurosci, 2010, 11(4): 227-238.

[15] Richard P Shank, Gudrun S Bennett, Svend O Freytag, et al. Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools[J]. Brain Res, 1985, 329(1-2):364–367.

[16] Niels C Danbolt. Glutamate uptake[J]. Prog Neurobiol, 2001, 65(1): 1-105.

[17] Martinez-Hernandez A, Bell K P, Michael Norenberg. Glutamine synthetase: glial localization in brain[J]. Science, 1977, 195(4284): 1356-1358.

[18] Dennis S C, James C K Lai, Clark J B. Comparative studies on glutamate metabolism in synpatic and non-synaptic rat brain mitochondria[J]. Biochem J, 1977, 164(3): 727-736.

[19] Farrukh A Chaudhry, Richard J Reimer, Robert H Edwards. The glutamine commute take the N line and transfer to the A[J]. J Cell Biol, 2002, 157(3): 349-355.

[20] Tom Tallak Solbu, Mona Bjørkmo, Paul Berghuis, et al. SAT1, a glutamine transporter, is preferentially expressed in GABAergic neurons[J]. Frontiers in Neuroanatomy, 2010, 4: 1.

[21] Monica Jenstad, Abrar Zaheer Quazi, Misha Zilberter, et al. System A transporter SAT2 mediates replenishment of dendritic glutamate pools controlling retrograde signaling by glutamate[J]. Cerebral Cortex, 2009, 19(5): 1092-1106.

[22] Elling Kvamme, Ingeborg Aa Torgner, Bjorg Roberg. Kinetics and localization of brain phosphate activated glutaminase[J]. J Neurosci Res, 2001, 66(5): 951-958.

[23] Robert T Fremeau, Jonathon Burman, Tayyaba Qureshi, et al. The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate[J]. Proceedings National Academy of Sciences, 2002, 99(22): 14488-14493.

[24] Shigeo Takamori, Pari Malherbe, Clemens Broger, et al. Molecular cloning and functional characterization of human vesicular glutamate transporter 3[J]. EMBO Reports, 2002, 3(8): 798-803.

[25] Fremeau R T, Burman J, Qureshi T, et al. The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate[J]. Proceedings of the National Academy of Sciences, 2002, 99(22): 14488-14493.

[26] Bu D F, Erlander M G, Hitz B C, et al. Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene[J]. Proc Natl Acad Sci USA, 1992, 89(6): 2115-2119.

[27] Jin H, Wu H, Osterhaus G, et al. Demonstration of functional coupling between gamma -aminobutyric acid (GABA) synthesis and vesicular GABA transport into synaptic vesicles[J]. Proc Natl Acad Sci USA, 2003, 100: 4293-4298.

[28] Lamigeon C, Bellier J P, Sacchettoni S, et al. Enhanced neuronal protection from oxidative stress by coculture with glutamic acid decarboxylase‐expressing astrocytes[J]. J Neurochemistry, 2001, 77(2): 598-606.

[29] Pinal C S, Allan Tobin. Uniqueness and redundancy in GABA production[J]. Perspect Dev Neurobiol, 1998, 5(2-3): 109-118.

[30] Helle Waagepetersen, Ursula Sonnewald, A Schousboe. The GABA paradox: multiple roles as metabolite, neurotransmitter, and neurodifferentiative agent[J].Neurochem, 1999, 73(4):1335-1342.

[31] Volker Eulenburg, Jesus Gomeza. Neurotransmitter transporters expressed in glial cells as regulators of synapse function[J]. Brain Res Rev, 2010, 63(1): 103-112. [32] Stefanie Robel, Benedikt Berninger, Magdalena Götz. The stem cell potential of glia: lessons from reactive gliosis[J]. Nature Reviews Neuroscience, 2011, 12(2): 88-104.

[33] Boison D. Epilepsy[M]. In: Kettenmann H, Ransom B R, editors. Neuroglia. 3 ed. New York: Oxford University Press; 2013: 896–905.

[34] Du Fu, William O Whetsell, Bassel Abou-Khalil, et al. Preferential neuronal loss in layer III of the entorhinal cortex in patients with temporal lobe epilepsy[J]. Epilepsy Res, 1993, 16(3): 223-233.

[35] Gloor P. Mesial temporal sclerosis: historical background and an overview from a modern perspective[J]. Leiter Performance Scale-Revised, 1997: 689-703.

[36] Wilhelm Sommer. Erkrankung des Ammonshorns als aetiologisches Moment der Epilepsie[J]. Archiv Psychiatry Clinical Neuroscience, 1880, 10(3): 631-675.

[37] Idil Cavus, Willard Stein Kasoff, Michael P Cassaday, et al. Extracellular metabolites in the cortex and hippocampus of epileptic patients[J]. Ann Neurol, 2005, 57(2): 226-235.

[38] Ben-Ari Y. Limbic seizure and brain damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy[J]. Neuroscience, 1985, 14(2): 375-403.

[39] Matthew During, Spencer D D. Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain[J]. Lancet, 1993, 341(8861): 1607-1610.

[40] Tore Eid, Nathan Tu, Tih-Shih W Lee, et al. Regulation of astrocyte glutamine synthetase in epilepsy[J]. Neurochem Int, 2013, 63(7): 670-681.

[41] W Saskia Van der Hel, Robert G E Notenboom, Bos I W M, et al. Reduced glutamine synthetase in hippocampal areas with neuron loss in temporal lobe epilepsy[J]. Neurology, 2005, 64(2): 326-333.

[42] Wang Yue, Hitten P Zaveri, Tih-Shih W Lee, et al. The development of recurrent seizures after continuous intrahippocampal infusion of methionine sulfoximine in rats: a video-intracranial electroencephalographic study[J]. Exp Neurol, 2009, 220(2): 293-302.

[43] Gauri H Malthankar‐Phatak, Nihal De Lanerolle, Tore Eid, et al. Differential glutamate dehydrogenase (GDH) activity profile in patients with temporal lobe epilepsy[J]. Epilepsia, 2006, 47(8): 1292-1299.

[44] Thomas S Otis, Craig E Jahr. Anion currents and predicted glutamate flux through a neuronal glutamate transporter[J]. J Neurosci, 1998, 18(18): 7099-7110.

[45] Javier Vaquero, Chu-han Chung, Andres T Blei. Brain edema in acute liver failure. A window to the pathogenesis of hepatic encephalopathy[J]. Ann Hepatol, 2003, 2(1): 12-22.

[46] Tore Eid, Arko Ghosh, Wang Yue, et al. Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats[J]. Brain, 2008, 131(8): 2061-2070.

[47] Johannes Häberle, Boris Görg, Annick Toutain, et al. Inborn error of amino acid synthesis: human glutamine synthetase deficiency[J]. J Inherited Metabolic Disease, 2006, 29(2-3): 352-358.

[48] Gauri H Malthankar‐Phatak, Nihal De Lanerolle, Tore Eid, et al. Differential glutamate dehydrogenase (GDH) activity profile in patients with temporal lobe epilepsy[J]. Epilepsia, 2006, 47(8): 1292-1299.

[49] Tanaka K, Watase K, Manabe T, et al. Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1[J]. Science, 1997, 276(5319): 1699-1702.

[50] Takemi Watanabe, Kiyoshi Morimoto, Toru Hirao, et al. Amygdala-kindled and pentylenetetrazole-induced seizures in glutamate transporter GLAST-deficient mice[J]. Brain Res, 1999, 845(1): 92-96.

[51] Tih-Shih Lee, Lars Petter Bjørnsen, Carlos Paz, et al. GAT1 and GAT3 expression are differently localized in the human epileptogenic hippocampus[J]. Acta Neuropatholog, 2006, 111(4): 351-363.

[52] Tore Eid, Nathan Tu, Tih-Shih W Lee, et al. Regulation of astrocyte glutamine synthetase in epilepsy[J]. Neurochem Int, 2013, 63(7): 670-681.

[53] Jennifer Shih, Liu Lei, Andrew Mason, et al. Loss of SIRT4 decreases GLT‐1‐dependent glutamate uptake and increases sensitivity to kainic acid[J]. J Neurochem, 2014, 131(5): 573-581.