Possibility that the Onset of Autism Spectrum Disorder is Induced by Failure of the Glutamine-Glutamate Cycle

Author(s): Koichi Kawada*, Nobuyuki Kuramoto, Seisuke Mimori

Journal Name: Current Molecular Pharmacology

Volume 14 , Issue 2 , 2021


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Autism spectrum disorder (ASD) is a neurodevelopmental disease, and the number of patients has increased rapidly in recent years. The causes of ASD involve both genetic and environmental factors, but the details of causation have not yet been fully elucidated. Many reports have investigated genetic factors related to synapse formation, and alcohol and tobacco have been reported as environmental factors. This review focuses on endoplasmic reticulum stress and amino acid cycle abnormalities (particularly glutamine and glutamate) induced by many environmental factors.

In the ASD model, since endoplasmic reticulum stress is high in the brain from before birth, it is clear that endoplasmic reticulum stress is involved in the development of ASD. On the other hand, one report states that excessive excitation of neurons is caused by the onset of ASD. The glutamine- glutamate cycle is performed between neurons and glial cells and controls the concentration of glutamate and GABA in the brain. These neurotransmitters are also known to control synapse formation and are important in constructing neural circuits. Theanine is a derivative of glutamine and a natural component of green tea. Theanine inhibits glutamine uptake in the glutamine-glutamate cycle via slc38a1 without affecting glutamate; therefore, we believe that theanine may prevent the onset of ASD by changing the balance of glutamine and glutamate in the brain.

Keywords: Autism spectrum disorder, glutamine-glutamate cycle, endoplasmic reticulum stress.

[1]
Kim, Y.S.; Leventhal, B.L.; Koh, Y.J.; Fombonne, E.; Laska, E.; Lim, E.C.; Cheon, K.A.; Kim, S.J.; Kim, Y.K.; Lee, H.; Song, D.H.; Grinker, R.R. Prevalence of autism spectrum disorders in a total population sample. Am. J. Psychiatry, 2011, 168(9), 904-912.
[http://dx.doi.org/10.1176/appi.ajp.2011.10101532] [PMID: 21558103]
[2]
Bolton, P.F.; Veltman, M.W.; Weisblatt, E.; Holmes, J.R.; Thomas, N.S.; Youings, S.A.; Thompson, R.J.; Roberts, S.E.; Dennis, N.R.; Browne, C.E.; Goodson, S.; Moore, V.; Brown, J. Chromosome 15q11-13 abnormalities and other medical conditions in individuals with autism spectrum disorders. Psychiatr. Genet., 2004, 14(3), 131-137.
[http://dx.doi.org/10.1097/00041444-200409000-00002] [PMID: 15318025]
[3]
Jamain, S.; Quach, H.; Betancur, C.; Råstam, M.; Colineaux, C.; Gillberg, I.C.; Soderstrom, H.; Giros, B.; Leboyer, M.; Gillberg, C.; Bourgeron, T. Paris Autism Research International Sibpair Study. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet., 2003, 34(1), 27-29.
[http://dx.doi.org/10.1038/ng1136] [PMID: 12669065]
[4]
Nakatani, J.; Tamada, K.; Hatanaka, F.; Ise, S.; Ohta, H.; Inoue, K.; Tomonaga, S.; Watanabe, Y.; Chung, Y.J.; Banerjee, R.; Iwamoto, K.; Kato, T.; Okazawa, M.; Yamauchi, K.; Tanda, K.; Takao, K.; Miyakawa, T.; Bradley, A.; Takumi, T. Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell, 2009, 137(7), 1235-1246.
[http://dx.doi.org/10.1016/j.cell.2009.04.024] [PMID: 19563756]
[5]
Dutta, S.; Das, S.; Guhathakurta, S.; Sen, B.; Sinha, S.; Chatterjee, A.; Ghosh, S.; Ahmed, S.; Ghosh, S.; Usha, R. Glutamate receptor 6 gene (GluR6 or GRIK2) polymorphisms in the Indian population: a genetic association study on autism spectrum disorder. Cell. Mol. Neurobiol., 2007, 27(8), 1035-1047.
[http://dx.doi.org/10.1007/s10571-007-9193-6] [PMID: 17712621]
[6]
Samaco, R.C.; Hogart, A.; LaSalle, J.M. Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum. Mol. Genet., 2005, 14(4), 483-492.
[http://dx.doi.org/10.1093/hmg/ddi045] [PMID: 15615769]
[7]
Adamsen, D.; Meili, D.; Blau, N.; Thöny, B.; Ramaekers, V. Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants. Mol. Genet. Metab., 2011, 102(3), 368-373.
[http://dx.doi.org/10.1016/j.ymgme.2010.11.162] [PMID: 21183371]
[8]
Uchino, S.; Wada, H.; Honda, S.; Nakamura, Y.; Ondo, Y.; Uchiyama, T.; Tsutsumi, M.; Suzuki, E.; Hirasawa, T.; Kohsaka, S. Direct interaction of post-synaptic density-95/Dlg/ZO-1 domain-containing synaptic molecule Shank3 with GluR1 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor. J. Neurochem., 2006, 97(4), 1203-1214.
[http://dx.doi.org/10.1111/j.1471-4159.2006.03831.x] [PMID: 16606358]
[9]
Tu, J.C.; Xiao, B.; Naisbitt, S.; Yuan, J.P.; Petralia, R.S.; Brakeman, P.; Doan, A.; Aakalu, V.K.; Lanahan, A.A.; Sheng, M.; Worley, P.F. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron, 1999, 23(3), 583-592.
[http://dx.doi.org/10.1016/S0896-6273(00)80810-7] [PMID: 10433269]
[10]
Uemura, T.; Mori, H.; Mishina, M. Direct interaction of GluRdelta2 with Shank scaffold proteins in cerebellar Purkinje cells. Mol. Cell. Neurosci., 2004, 26(2), 330-341.
[http://dx.doi.org/10.1016/j.mcn.2004.02.007] [PMID: 15207857]
[11]
Tobaben, S.; Südhof, T.C.; Stahl, B. The G protein-coupled receptor CL1 interacts directly with proteins of the Shank family. J. Biol. Chem., 2000, 275(46), 36204-36210.
[http://dx.doi.org/10.1074/jbc.M006448200] [PMID: 10958799]
[12]
Kawada, K.; Mimori, S.; Okuma, Y.; Nomura, Y. Involvement of endoplasmic reticulum stress and neurite outgrowth in the model mice of autism spectrum disorder. Neurochem. Int., 2018, 119, 115-119.
[http://dx.doi.org/10.1016/j.neuint.2017.07.004] [PMID: 28711654]
[13]
Kawada, K.; Iekumo, T.; Saito, R.; Kaneko, M.; Mimori, S.; Nomura, Y.; Okuma, Y. Aberrant neuronal differentiation and inhibition of dendrite outgrowth resulting from endoplasmic reticulum stress. J. Neurosci. Res., 2014, 92(9), 1122-1133.
[http://dx.doi.org/10.1002/jnr.23389] [PMID: 24723324]
[14]
O’Roak, B.J.; Vives, L.; Girirajan, S.; Karakoc, E.; Krumm, N.; Coe, B.P.; Levy, R.; Ko, A.; Lee, C.; Smith, J.D.; Turner, E.H.; Stanaway, I.B.; Vernot, B.; Malig, M.; Baker, C.; Reilly, B.; Akey, J.M.; Borenstein, E.; Rieder, M.J.; Nickerson, D.A.; Bernier, R.; Shendure, J.; Eichler, E.E. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature, 2012, 485(7397), 246-250.
[http://dx.doi.org/10.1038/nature10989] [PMID: 22495309]
[15]
Bradford, H.F.; Ward, H.K. On glutaminase activity in mammalian synaptosomes. Brain Res., 1976, 110(1), 115-125.
[http://dx.doi.org/10.1016/0006-8993(76)90212-2] [PMID: 1276943]
[16]
Sonnewald, U.; Westergaard, N.; Schousboe, A.; Svendsen, J.S.; Unsgård, G.; Petersen, S.B. Direct demonstration by [13C]NMR spectroscopy that glutamine from astrocytes is a precursor for GABA synthesis in neurons. Neurochem. Int., 1993, 22(1), 19-29.
[http://dx.doi.org/10.1016/0197-0186(93)90064-C] [PMID: 8095170]
[17]
Boulland, J.L.; Osen, K.K.; Levy, L.M.; Danbolt, N.C.; Edwards, R.H.; Storm-Mathisen, J.; Chaudhry, F.A. Cell-specific expression of the glutamine transporter SN1 suggests differences in dependence on the glutamine cycle. Eur. J. Neurosci., 2002, 15(10), 1615-1631.
[http://dx.doi.org/10.1046/j.1460-9568.2002.01995.x] [PMID: 12059969]
[18]
Varoqui, H.; Zhu, H.; Yao, D.; Ming, H.; Erickson, J.D. Cloning and functional identification of a neuronal glutamine transporter. J. Biol. Chem., 2000, 275(6), 4049-4054.
[http://dx.doi.org/10.1074/jbc.275.6.4049] [PMID: 10660562]
[19]
Mackenzie, B.; Schäfer, M.K.; Erickson, J.D.; Hediger, M.A.; Weihe, E.; Varoqui, H. Functional properties and cellular distribution of the system A glutamine transporter SNAT1 support specialized roles in central neurons. J. Biol. Chem., 2003, 278(26), 23720-23730.
[http://dx.doi.org/10.1074/jbc.M212718200] [PMID: 12684517]
[20]
Qureshi, T.; Sørensen, C.; Berghuis, P.; Jensen, V.; Dobszay, M.B.; Farkas, T.; Dalen, K.T.; Guo, C.; Hassel, B.; Utheim, T.P.; Hvalby, Ø.; Hafting, T.; Harkany, T.; Fyhn, M.; Chaudhry, F.A. The Glutamine Transporter Slc38a1 Regulates GABAergic Neurotransmission and Synaptic Plasticity. Cereb. Cortex, 2019, 29(12), 5166-5179.
[http://dx.doi.org/10.1093/cercor/bhz055] [PMID: 31050701]
[21]
Mackenzie, B.; Erickson, J.D. Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family. Pflugers Arch., 2004, 447(5), 784-795.
[http://dx.doi.org/10.1007/s00424-003-1117-9] [PMID: 12845534]
[22]
Désir-Vigné, A.; Haure-Mirande, V.; de Coppet, P.; Darmaun, D.; Le Dréan, G.; Segain, J.P. Perinatal supplementation of 4-phenylbutyrate and glutamine attenuates endoplasmic reticulum stress and improves colonic epithelial barrier function in rats born with intrauterine growth restriction. J. Nutr. Biochem., 2018, 55, 104-112.
[http://dx.doi.org/10.1016/j.jnutbio.2017.12.007] [PMID: 29413485]
[23]
Zieminska, E.; Toczylowska, B.; Diamandakis, D.; Hilgier, W.; Filipkowski, R.K.; Polowy, R.; Orzel, J.; Gorka, M.; Lazarewicz, J.W. Glutamate, Glutamine and GABA Levels in Rat Brain Measured Using MRS, HPLC and NMR Methods in Study of Two Models of Autism. Front. Mol. Neurosci., 2018, 11, 418.
[http://dx.doi.org/10.3389/fnmol.2018.00418] [PMID: 30505268]
[24]
Mimori, S.; Ohtaka, H.; Koshikawa, Y.; Kawada, K.; Kaneko, M.; Okuma, Y.; Nomura, Y.; Murakami, Y.; Hamana, H. 4-Phenylbutyric acid protects against neuronal cell death by primarily acting as a chemical chaperone rather than histone deacetylase inhibitor. Bioorg. Med. Chem. Lett., 2013, 23(21), 6015-6018.
[http://dx.doi.org/10.1016/j.bmcl.2013.08.001] [PMID: 24044874]
[25]
Fujiwara, M.; Yamamoto, H.; Miyagi, T.; Seki, T.; Tanaka, S.; Hide, I.; Sakai, N. Effects of the chemical chaperone 4-phenylbutylate on the function of the serotonin transporter (SERT) expressed in COS-7 cells. J. Pharmacol. Sci., 2013, 122(2), 71-83.
[http://dx.doi.org/10.1254/jphs.12194FP] [PMID: 23676312]
[26]
Fujita, E.; Dai, H.; Tanabe, Y.; Zhiling, Y.; Yamagata, T.; Miyakawa, T.; Tanokura, M.; Momoi, M.Y.; Momoi, T. Autism spectrum disorder is related to endoplasmic reticulum stress induced by mutations in the synaptic cell adhesion molecule, CADM1. Cell Death Dis., 2010, 1, e47.
[http://dx.doi.org/10.1038/cddis.2010.23] [PMID: 21364653]
[27]
Ruch, A.; Kurczynski, T.W.; Velasco, M.E. Mitochondrial alterations in Rett syndrome. Pediatr. Neurol., 1989, 5(5), 320-323.
[http://dx.doi.org/10.1016/0887-8994(89)90027-1] [PMID: 2803392]
[28]
Wakai, S.; Kameda, K.; Ishikawa, Y.; Miyamoto, S.; Nagaoka, M.; Okabe, M.; Minami, R.; Tachi, N. Rett syndrome: findings suggesting axonopathy and mitochondrial abnormalities. Pediatr. Neurol., 1990, 6(5), 339-343.
[http://dx.doi.org/10.1016/0887-8994(90)90028-Y] [PMID: 2242177]
[29]
Dotti, M.T.; Manneschi, L.; Malandrini, A.; De Stefano, N.; Caznerale, F.; Federico, A. Mitochondrial dysfunction in Rett syndrome. An ultrastructural and biochemical study. Brain Dev., 1993, 15(2), 103-106.
[http://dx.doi.org/10.1016/0387-7604(93)90045-A] [PMID: 8214327]
[30]
Cornford, M.E.; Philippart, M.; Jacobs, B.; Scheibel, A.B.; Vinters, H.V. Neuropathology of Rett syndrome: case report with neuronal and mitochondrial abnormalities in the brain. J. Child Neurol., 1994, 9(4), 424-431.
[http://dx.doi.org/10.1177/088307389400900419] [PMID: 7822737]
[31]
Eeg-Olofsson, O.; al-Zuhair, A.G.; Teebi, A.S.; al-Essa, M.M. Rett syndrome: genetic clues based on mitochondrial changes in muscle. Am. J. Med. Genet., 1989, 32(1), 142-144.
[http://dx.doi.org/10.1002/ajmg.1320320131] [PMID: 2705475]
[32]
Coker, S.B.; Melnyk, A.R. Rett syndrome and mitochondrial enzyme deficiencies. J. Child Neurol., 1991, 6(2), 164-166.
[http://dx.doi.org/10.1177/088307389100600216] [PMID: 1646255]
[33]
Heilstedt, H.A.; Shahbazian, M.D.; Lee, B. Infantile hypotonia as a presentation of Rett syndrome. Am. J. Med. Genet., 2002, 111(3), 238-242.
[http://dx.doi.org/10.1002/ajmg.10633] [PMID: 12210319]
[34]
Sierra, C.; Vilaseca, M.A.; Brandi, N.; Artuch, R.; Mira, A.; Nieto, M.; Pineda, M. Oxidative stress in Rett syndrome. Brain Dev., 2001, 23(Suppl. 1), S236-S239.
[http://dx.doi.org/10.1016/S0387-7604(01)00369-2] [PMID: 11738881]
[35]
De Felice, C.; Ciccoli, L.; Leoncini, S.; Signorini, C.; Rossi, M.; Vannuccini, L.; Guazzi, G.; Latini, G.; Comporti, M.; Valacchi, G.; Hayek, J. Systemic oxidative stress in classic Rett syndrome. Free Radic. Biol. Med., 2009, 47(4), 440-448.
[http://dx.doi.org/10.1016/j.freeradbiomed.2009.05.016] [PMID: 19464363]
[36]
Jin, L.W.; Horiuchi, M.; Wulff, H.; Liu, X.B.; Cortopassi, G.A.; Erickson, J.D.; Maezawa, I. Dysregulation of glutamine transporter SNAT1 in Rett syndrome microglia: a mechanism for mitochondrial dysfunction and neurotoxicity. J. Neurosci., 2015, 35(6), 2516-2529.
[http://dx.doi.org/10.1523/JNEUROSCI.2778-14.2015] [PMID: 25673846]
[37]
Hutchins, J.B.; Barger, S.W. Why neurons die: cell death in the nervous system. Anat. Rec., 1998, 253(3), 79-90.
[http://dx.doi.org/10.1002/(SICI)1097-0185(199806)253:3<79::AID-AR4>3.0.CO;2-9] [PMID: 9700393]
[38]
Barger, S.W.; Goodwin, M.E.; Porter, M.M.; Beggs, M.L. Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation. J. Neurochem., 2007, 101(5), 1205-1213.
[http://dx.doi.org/10.1111/j.1471-4159.2007.04487.x] [PMID: 17403030]
[39]
Lonsdale, D.; Shamberger, R.J.; Audhya, T. Treatment of autism spectrum children with thiamine tetrahydrofurfuryl disulfide: a pilot study. Neuroendocrinol. Lett., 2002, 23(4), 303-308.
[PMID: 12195231]
[40]
Momeni, N.; Nordström, B.M.; Horstmann, V.; Avarseji, H.; Sivberg, B.V. Alterations of prolyl endopeptidase activity in the plasma of children with autistic spectrum disorders. BMC Psychiatry, 2005, 5, 27.
[http://dx.doi.org/10.1186/1471-244X-5-27] [PMID: 15932649]
[41]
Pan, C.; Prentice, H.; Price, A.L.; Wu, J.Y. Beneficial effect of taurine on hypoxia- and glutamate-induced endoplasmic reticulum stress pathways in primary neuronal culture. Amino Acids, 2012, 43(2), 845-855.
[http://dx.doi.org/10.1007/s00726-011-1141-6] [PMID: 22080215]
[42]
Van Laar, V.S.; Roy, N.; Liu, A.; Rajprohat, S.; Arnold, B.; Dukes, A.A.; Holbein, C.D.; Berman, S.B. Glutamate excitotoxicity in neurons triggers mitochondrial and endoplasmic reticulum accumulation of Parkin, and, in the presence of N-acetyl cysteine, mitophagy. Neurobiol. Dis., 2015, 74, 180-193.
[http://dx.doi.org/10.1016/j.nbd.2014.11.015] [PMID: 25478815]
[43]
Li, Y.; Li, J.; Li, S.; Li, Y.; Wang, X.; Liu, B.; Fu, Q.; Ma, S. Curcumin attenuates glutamate neurotoxicity in the hippocampus by suppression of ER stress-associated TXNIP/NLRP3 inflammasome activation in a manner dependent on AMPK. Toxicol. Appl. Pharmacol., 2015, 286(1), 53-63.
[http://dx.doi.org/10.1016/j.taap.2015.03.010] [PMID: 25791922]
[44]
Win-Shwe, T.T.; Nway, N.C.; Imai, M.; Lwin, T.T.; Mar, O.; Watanabe, H. Social behavior, neuroimmune markers and glutamic acid decarboxylase levels in a rat model of valproic acid-induced autism. J. Toxicol. Sci., 2018, 43(11), 631-643.
[http://dx.doi.org/10.2131/jts.43.631] [PMID: 30404997]
[45]
Horder, J.; Petrinovic, M.M.; Mendez, M.A.; Bruns, A.; Takumi, T.; Spooren, W.; Barker, G.J.; Künnecke, B.; Murphy, D.G. Glutamate and GABA in autism spectrum disorder-a translational magnetic resonance spectroscopy study in man and rodent models. Transl. Psychiatry, 2018, 8(1), 106.
[http://dx.doi.org/10.1038/s41398-018-0155-1] [PMID: 29802263]
[46]
Singh, S.K.; Stogsdill, J.A.; Pulimood, N.S.; Dingsdale, H.; Kim, Y.H.; Pilaz, L.J.; Kim, I.H.; Manhaes, A.C.; Rodrigues, W.S., Jr; Pamukcu, A.; Enustun, E.; Ertuz, Z.; Scheiffele, P.; Soderling, S.H.; Silver, D.L.; Ji, R.R.; Medina, A.E.; Eroglu, C. Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin. Cell, 2016, 164(1-2), 183-196.
[http://dx.doi.org/10.1016/j.cell.2015.11.034] [PMID: 26771491]
[47]
Kang, D.W.; Adams, J.B.; Gregory, A.C.; Borody, T.; Chittick, L.; Fasano, A.; Khoruts, A.; Geis, E.; Maldonado, J.; McDonough-Means, S.; Pollard, E.L.; Roux, S.; Sadowsky, M.J.; Lipson, K.S.; Sullivan, M.B.; Caporaso, J.G.; Krajmalnik-Brown, R. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome, 2017, 5(1), 10.
[http://dx.doi.org/10.1186/s40168-016-0225-7] [PMID: 28122648]
[48]
Leber, A.; Hontecillas, R.; Tubau-Juni, N.; Zoccoli-Rodriguez, V.; Abedi, V.; Bassaganya-Riera, J. NLRX1 Modulates Immunometabolic Mechanisms Controlling the Host-Gut Microbiota Interactions during Inflammatory Bowel Disease. Front. Immunol., 2018, 9, 363.
[http://dx.doi.org/10.3389/fimmu.2018.00363] [PMID: 29535731]
[49]
Yoneda, Y. An L-Glutamine Transporter Isoform for Neurogenesis Facilitated by L-Theanine. Neurochem. Res., 2017, 42(10), 2686-2697.
[http://dx.doi.org/10.1007/s11064-017-2317-6] [PMID: 28597057]
[50]
Bradstreet, J.J.; Ruggiero, M.; Pacini, S. Commentary: Structural and functional features of central nervous system lymphatic vessels. Front. Neurosci., 2015, 9, 485.
[http://dx.doi.org/10.3389/fnins.2015.00485] [PMID: 26733797]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 14
ISSUE: 2
Year: 2021
Published on: 19 March, 2020
Page: [170 - 174]
Pages: 5
DOI: 10.2174/1874467213666200319125109
Price: $65

Article Metrics

PDF: 73
HTML: 5
PRC: 1