GABA and Glutamate Imbalance in Autism and Their Reversal as Novel Hypothesis for Effective Treatment Strategy



Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by reduced social communication and repetitive behaviors. The etiological mechanisms of ASD are still unknown; however, the GABAergic system has received considerable attention due to its potential as a therapeutic target. Based on the fact that individuals with autism demonstrate altered gene expression concomitant with impaired blood brain barrier (BBB), and gut barrier integrities, so increased glutamate levels in the blood and platelets of ASD patients can be related to lower numbers of cerebellar GABAergic neurons, less active GABA-synthesizing enzymes, and decreased brain GABA levels. Excitotoxic levels of released glutamate trigger a cascade of deleterious cellular events leading to delayed neuronal death. According to our understanding of glutamate excitotoxicity, GABA supplementation could theoretically be useful to treat certain autistic phenotypes. While there is still no effective and safe medication for glutamate-related cell damage and death, combined efforts will hopefully develop better treatment options. Here I hypothesize that an integrated treatment strategy with GABA supplements, regulation of chloride (Cl-) and magnesium (Mg2+) levels, vitamin D supplements, probiotics to enhance GABAA receptor and glutamate decarboxylase (GAD) expression, and memantine to activate glutamate transporters and inhibit NMDA receptors, could collectively reduce glutamate levels, maintain functional GABA receptors and thus treat repetitive behavior, impaired social behavior, and seizure activity in individuals with autism.

General Information

Keywords: autism; glutamate excitotoxicity; gamma-aminobutyric acid; vitamin D; gut microbiota

Journal rubric: Research & Diagnosis of ASD


Funding. This project was funded by the National Plan for Science Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia, Award number: 08-MED 510-02

Acknowledgements. The author thank the Deanship of Scientific Research and RSSU at King Saud University for their technical support.” Special thanks for Mrs Ramesa Shafi Bhat, Biochemistry Department, College of Science, KSU for her great efforts in improving the manuscript

For citation: El-Ansary A. GABA and Glutamate Imbalance in Autism and Their Reversal as Novel Hypothesis for Effective Treatment Strategy. Autizm i narusheniya razvitiya = Autism and Developmental Disorders, 2020. Vol. 18, no. 3, pp. 46–63. DOI: 10.17759/autdd.2020180306.


  1. Adams J.B. et al. Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity. Nutrition & metabolism, 2011, vol. 8, no. 1, p. 34. DOI: 10.1186/1743-7075-8-34
  2. Alfawaz H., Tamim H., Alharbi S., Aljaser S., Tamimi W. Vitamin D status among patients visiting a tertiary care center  in Riyadh, Saudi Arabia: a retrospective review of 3475 cases. BMC public health, 2014, vol. 14, no. 1, p. 159. DOI: 10.1186/1471-2458-14-159
  3. Al-Suwailem E., Abdi S., Bhat R.S., El-Ansary A. Glutamate Signaling Defects in Propionic Acid Orally Administered to Juvenile Rats as an Experimental Animal Model of Autism. Neurochemical Journal, 2019, vol. 13, no. 1, pp. 90—98. DOI: 10.1134/S1819712419010021
  4. Anderson C.M., Swanson R.A. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia, 2000, vol. 32, no. 1, pp. 1—14.
  5. Angelova P.R., Abramov A.Y. Role of mitochondrial ROS in the brain: from physiology to neurodegeneration. FEBS letters, 2018, vol. 592, no. 5, pp. 692—702. DOI: 10.1002/1873-3468.12964
  6. Aoki Y., Cortese S. Mitochondrial aspartate/glutamate carrier SLC25A12 and autism spectrum disorder: a meta-analysis. Molecular neurobiology, 2016, vol. 53, no. 3, pp. 1579—1588. DOI: 10.1007/s12035-015-9116-3
  7. Ashwood P., Hughes H.K. Brief Report: Anti-Candida albicans IgG antibodies in children with autism spectrum disorders. Frontiers in psychiatry, 2018, vol. 9, p. 627. DOI: 10.3389/fpsyt.2018.00627
  8. Bailey A. et al. A clinicopathological study of autism. Brain: a journal of neurology, 1998, vol. 121, no. 5, pp. 889—905. DOI:   10.1093/brain/121.5.889
  9. Barrett E., Ross R.P., O’Toole P.W., Fitzgerald G.F., Stanton C. γ-Aminobutyric acid production by culturable bacteria from the human intestine [correction published in: Journal of applied microbiology, 2014, vol. 116, no. 5, pp. 1384—1386]. Journal of applied microbiology, 2012, vol. 113, no. 2, pp. 411—417. DOI: 10.1111/j.1365-2672.2012.05344.x
  10. Ben-Ari Y. The GABA excitatory/inhibitory developmental sequence: a personal journey. Neuroscience, 2014, vol. 279, pp.  187—219.  DOI: 10.1016/j.neuroscience.2014.08.001
  11. Bezzi P. et al. CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity. Nature neuroscience, 2001, vol. 4, no. 7, pp. 702—710. DOI: 10.1038/89490
  12. Bilbo S.D., Schwarz J.M. Early-life programming of later-life brain and behavior: a critical role for the immune  system. Frontiers in behavioral neuroscience, 2009, vol. 3, p. 14. DOI: 10.3389/neuro.08.014.2009
  13. Bilbo S.D., Smith S.H., Schwarz J.M. A lifespan approach to neuroinflammatory and cognitive disorders: a critical role for glia. Journal of Neuroimmune Pharmacology, 2012, vol. 7, no. 1, pp. 24—41. DOI: 10.1007/s11481-011-9299-y
  14. Biou V., Bhattacharyya S., Malenka R.C. Endocytosis and recycling of AMPA receptors lacking GluR2/3. Proceedings of the National Academy of Sciences of the United States of America, 2008, vol. 105, no. 3, pp. 1038—1043. DOI: 10.1073/ pnas.0711412105
  15. Blatt G.J. et al. Density  and  distribution  of  hippocampal  neurotransmitter  receptors  in  autism:  an autoradiographic study. Journal of autism and developmental disorders, 2001, vol. 31, no. 6, pp. 537—543. DOI: 10.1023/a:1013238809666
  16. Boonstra E., de Kleijn R., Colzato L.S., Alkemade A., Forstmann B.U., Nieuwenhuis S. Neurotransmitters as food supplements: the effects of GABA on brain and behavior. Frontiers in Psychology, 2015, vol. 6, p. 1520. DOI: 10.3389/ fpsyg.2015.01520
  17. Borisova T. et al. Effects of new fluorinated analogues of GABA, pregabalin bioisosters, on the ambient level and exocytotic release of [(3)H]GABA from rat brain nerve terminals. Bioorganic & Medicinal Chemistry, 2017, vol. 25, no. 2, pp. 759— 764. DOI: 10.1016/j.bmc.2016.11.052
  18. Borisova T. Nervous System Injury in Response to Contact With Environmental, Engineered and Planetary Micro- and Nano-Sized Particles. Frontiers in Physiology, 2018, vol. 9, p. 728. DOI: 10.3389/fphys.2018.00728
  19. Borisova T. Permanent dynamic transporter-mediated turnover of glutamate across the plasma membrane of presynaptic nerve terminals: arguments in favor and against. Reviews in the Neurosciences, 2016, vol. 27, no. 1, pp. 71—81. DOI: 10.1515/revneuro-2015-0023
  20. Borisova T., Borysov A. Putative duality of presynaptic events. Reiews in the Neurosciences, 2016, vol. 27, no. 4, pp. 377— 383.  DOI:  10.1515/revneuro-2015-0044
  21. Bravo J.A. et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences of the United States of America, 2011, vol. 108, no. 38, pp. 16050—16055. DOI: 10.1073/pnas.1102999108
  22. Brown M.S., Singel D., Hepburn S., Rojas D.C. Increased glutamate concentration in the auditory cortex of persons with autism and first-degree relatives: a (1)H-MRS study. Autism Research, 2013, vol. 6, no. 1, pp. 1—10. DOI: 10.1002/ aur.1260
  23. Bruchhage M.K., Bucci M.-P., Becker E.B.E. Cerebellar involvement in autism and ADHD. Handbook of clinical neurology, 2018, vol. 155, pp. 61—72. DOI: 10.1016/B978-0-444-64189-2.00004-4
  24. Burrus C J. A biochemical rationale for the interaction between gastrointestinal yeast and autism. Medical Hypotheses, 2012, vol. 79, no. 6, pp. 784—785. DOI: 10.1016/j.mehy.2012.08.029
  25. Canitano R., Pallagrosi M. Autism spectrum disorders and schizophrenia spectrum disorders: excitation/inhibition imbalance and developmental trajectories. Frontiers in psychiatry, 2017, vol. 8, p. 69. DOI: 10.3389/fpsyt.2017.00069
  26. Caraiscos V.B. et al. Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing γ-aminobutyric acid type A receptors. Proceedings of the National Academy of Sciences of the United States of America, 2004, vol. 101, no. 10, pp. 3662—3667. DOI: 10.1073/pnas.0307231101
  27. Cellot G., Cherubini E. GABAergic signaling as therapeutic target for autism spectrum disorders. Frontiers in pediatrics, 2014, vol. 2, p. 70. DOI: 10.3389/fped.2014.00070
  28. Chebib M., Johnston G.A. The ‘ABC’ of GABA receptors: a brief review. Clinical and experimental pharmacology and physiology, 1999, vol. 26, no. 11, pp. 937—940. DOI: 10.1046/j.1440-1681.1999.03151.x
  29. Cohen B.I. GABA-transaminase, the liver and infantile autism. Medical Hypotheses, 2001, vol. 57, no. 6, pp. 673—674. DOI:  10.1054/mehy.2001.1350
  30. Côme E., Marques X., Poncer J.C., Lévi S. Neuronal protein mobility KCC2 membrane diffusion tunes neuronal chloride homeostasis. Neuropharmacology, 2020, vol. 169. DOI: 10.1016/j.neuropharm.2019.03.014
  31. Cull-Candy S., Kelly L., Farrant M. Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond. Current opinion in neurobiology, 2006, vol. 16, no. 3, pp. 288—297. DOI: 10.1016/j.conb.2006.05.012
  32. Daghestani M.H. et al. The role of apitoxin in alleviating propionic acid-induced neurobehavioral impairments in rat pups: the expression pattern of Reelin gene. Biomedicine & Pharmacotherapy, 2017, vol. 93, pp. 48—56.
  33. Dhossche D. et al. Elevated plasma gamma-aminobutyric acid (GABA) levels in autistic youngsters: stimulus for a GABA hypothesis of autism. Medical Science Monitor, 2002, vol. 8, no. 8, pp. PR1—PR6.
  34. Diagnostic and statistical manual of mental disorders: DSM-5. 5th edition. Arlington: Publ. American Psychiatric Publishing, 2013. ISBN 978-0-89042-555-8.
  35. Duarte S.T. et al. Abnormal expression of cerebrospinal fluid cation chloride cotransporters in patients with Rett syndrome. PLoS One, 2013, vol. 8, no. 7, article no. e68851. DOI: 10.1371/journal.pone.0068851
  36. Edfawy M. et al. Abnormal mGluR-mediated synaptic plasticity and autism-like behaviours in Gprasp2 mutant mice. Nature Communications, 2019, vol. 10, no. 1, p. 1431. DOI: 10.1038/s41467-019-09382-9
  37. Edmiston E., Ashwood P., Van de Water J. Autoimmunity, autoantibodies, and autism spectrum disorder. Biological psychiatry, 2017, vol. 81, no. 5, pp. 383—390. DOI: 10.1016/j.biopsych.2016.08.031
  38. Egerton A. et al. Anterior cingulate glutamate levels related to clinical status following treatment in first-episode schizophrenia. Neuropsychopharmacology, 2012, vol. 37, no. 11, pp. 2515—2521. DOI: 10.1038/npp.2012.113
  39. El-Ansary A. Data of multiple regressions analysis between selected biomarkers related to glutamate excitotoxicity and oxidative stress in Saudi autistic patients. Data in brief, 2016, vol. 7, pp. 111—116. DOI: 10.1016/j.dib.2016.02.025
  40. El-Ansary A. et al. In the search for reliable biomarkers for the early diagnosis of autism spectrum disorder: the role of vitamin D. Metabolic brain disease, 2018, vol. 33, no. 3, pp. 917—931. DOI: 10.1007/s11011-018-0199-1
  41. El-Ansary A. et al. Probiotic treatment reduces the autistic-like excitation/inhibition imbalance in juvenile hamsters induced by orally administered propionic acid and clindamycin. Metabolic brain disease, 2018, vol. 33, no. 4, pp. 1155— 1164. DOI: 10.1007/s11011-018-0212-8
  42. El-Ansary A., Al-Ayadhi L. GABAergic/glutamatergic imbalance relative to excessive neuroinflammation in autism spectrum disorders. Journal of Neuroinflammation, 2014, vol. 11, p. 189. DOI: 10.1186/s12974-014-0189-0
  43. El-Ansary A., Al-Salem H.S., Asma A., Al-Dbass A. Glutamate excitotoxicity induced by orally administered propionic  acid, a short chain fatty acid can be ameliorated by bee pollen. Lipids in health and disease, 2017, vol. 16, no. 1, p. 96. DOI: 10.1186/s12944-017-0485-7
  44. Essa M.M., Braidy N., Subash S., Vijayan R.K., Guillemin G.J. Excitotoxicity in the Pathogenesis of Autism. In Kostrzewa R.M. (ed.) Handbook of Neurotoxicity. Springer, New York: Publ. Springer, 2014. 636 p. ISBN 978-1- 46145835-7.
  45. Eyles D.W. Vitamin D and autism: does skin colour modify risk? Acta paediatrica, 2010, vol. 99, no. 5, pp. 645—647. DOI: 10.1111/j.1651-2227.2010.01797.x
  46. Fatemi S.H. et al. Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biological Psychiatry, 2002, vol. 52, no. 8, pp. 805—810. DOI: 10.1016/s0006-3223(02)01430-0
  47. Fatemi S.H. The hyperglutamatergic hypothesis of autism. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2008, vol. 32, no. 3, p. 911 [author reply 912—913]. DOI: 10.1016/j.pnpbp.2007.11.004
  48. Felipo V., Butterworth R.F. Neurobiology of ammonia. Progress in Neurobiology, 2002, vol. 67, no. 4, pp. 259—279. DOI: 10.1016/s0301-0082(02)00019-9
  49. Feng J. et al. Clinical improvement following vitamin D3 supplementation in autism spectrum disorder. Nutritional neuroscience, 2017, vol. 20, no. 5, pp. 284—290. DOI: 10.1080/1028415X.2015.1123847
  50. Ferguson A.R. et al. Group I metabotropic glutamate receptors control metaplasticity of spinal cord learning through a protein kinase C-dependent mechanism. Journal of Neuroscience, 2008, vol. 28, no. 46, pp. 11939—11949. DOI: 10.1523/ JNEUROSCI.3098-08.2008
  51. Fernell E. et al. Autism spectrum disorder and low vitamin D at birth: a sibling control study. Molecular autism, 2015, vol. 6, no. 1, p. 3. DOI: 10.1186/2040-2392-6-3
  52. Fiorentino M., Sapone A., Senger S. et al. Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Molecular Autism, 2016, vol. 7, p. 49. DOI:10.1186/s13229-016-0110-z
  53. Ford T.C., Abu-Akel A., Crewther D.P. The association of excitation and  inhibition  signaling  with  the  relative  symptom expression of autism and psychosis-proneness: Implications for psychopharmacology. Progress in Neuro- Psychopharmacology and Biological Psychiatry, 2019, vol. 88, pp. 235—242. DOI: 10.1016/j.pnpbp.2018.07.024
  54. Ford T.C., Nibbs R., Crewther D.P. Glutamate/GABA+ ratio is associated with the psychosocial domain of autistic and schizotypal traits. PloS one, 2017, vol. 12, no. 7, article no. e0181961. DOI: 10.1371/journal.pone.0181961
  55. Ford T.C., Nibbs R., Crewther D.P. Increased glutamate/GABA+ ratio in a shared autistic and schizotypal trait phenotype termed Social Disorganisation. NeuroImage: Clinical, 2017, vol. 16, pp. 125—131. DOI: 10.1016/j.nicl.2017.07.009
  56. Gegelashvili G., Bjerrum O.J. High-affinity glutamate transporters in chronic pain: an emerging therapeutic target. Journal of neurochemistry, 2014, vol. 131, no.6, pp. 712—730. DOI: 10.1111/jnc.12957
  57. Gong Z.-L. et al. Serum 25-hydroxyvitamin D levels in Chinese children with autism spectrum disorders. Neuroreport, 2014, vol. 25, no. 1, pp. 23—27. DOI: 10.1097/WNR.0000000000000034
  58. Grant  W.B.,  Cannell  J.J.  Autism prevalence in the United States with respect to solar UV-B doses: an ecological study. Dermato-endocrinology, 2013, vol. 5, no. 1, pp. 159—164. DOI: 10.4161/derm.22942
  59. Grewer C. et al. Individual subunits of the glutamate transporter EAAC1 homotrimer function independently of each other. Biochemistry, 2005, vol. 44, no. 35, pp. 11913—11923. DOI: 10.1021/bi050987n
  60. Groves N.J. et al. Adult vitamin D deficiency leads to behavioural and brain neurochemical alterations in C57BL/6J and BALB/c mice. Behavioural brain research, 2013, vol. 241, pp. 120—131. DOI: 10.1016/j.bbr.2012.12.001
  61. Han S., Tai C., Jones C.J., Scheuer T., Catterall W.A. Enhancement of inhibitory neurotransmission by GABAA receptors having α2, 3-subunits ameliorates behavioral deficits in a mouse model of autism. Neuron, 2014, vol. 81, no. 6, pp. 1282— 1289.  DOI:  10.1016/j.neuron.2014.01.016
  62. He Q., Nomura T., Xu J., Contractor A. The developmental switch in GABA polarity is delayed in fragile X mice. Journal of Neuroscience, 2014, vol. 34, no. 2, pp. 446—450. DOI: 10.1523/JNEUROSCI.4447-13.2014
  63. Hoernlein C. MSG and autism [Web resource]. 2019. URL: (Accessed 03.09.2020).
  64. Iovene M.R. et al. Intestinaldysbiosisandyeastisolationinstoolofsubjectswithautismspectrumdisorders. Mycopathologia, 2017, vol. 182, no. 3-4, pp. 349—363. DOI: 10.1007/s11046-016-0068-6
  65. Kemper T.L., Bauman M. Neuropathology of infantile autism. Journal of neuropathology and experimental neurology, 1998, vol. 57, no. 7, pp. 645—652. DOI: 10.1097/00005072-199807000-00001
  66. Knoflach  F.,  Hernandez  M.-C.,  Bertrand  D.  GABAA  receptor-mediated  neurotransmission:  Not  so  simple  after  all.  Biochemical pharmacology, 2016, vol. 115, pp. 10—17. DOI: 10.1016/j.bcp.2016.03.014
  67. Kočovská E., Gaughran F., Krivoy A., Meier U.C. Vitamin-D deficiency as a potential environmental risk factor in multiple sclerosis, schizophrenia, and autism. Frontiers in psychiatry, 2017, vol. 8, no. 47. DOI: 10.3389/fpsyt.2017.00047
  68. Koyama R., Ikegaya Y. Microglia in the pathogenesis of autism spectrum disorders. Neuroscience research, 2015, vol. 100, pp. 1—5. DOI:  10.1016/j.neures.2015.06.005
  69. Krisanova N. et al. Vitamin D3 deficiency in puberty rats causes presynaptic malfunctioning through alterations in exocytotic release and uptake of glutamate/GABA and expression of EAAC-1/GAT-3 transporters. Food and Chemical Toxicology, 2019, vol. 123, pp. 142—150. DOI: 10.1016/j.fct.2018.10.054
  70. Lee V., Maguire J. The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type. Frontiers in neural circuits, 2014, vol. 8, p. 3. DOI: 10.3389/fncir.2014.00003
  71. Leonoudakis D., Zhao P., Beattie E.C. Rapid tumor necrosis factor α-induced exocytosis of glutamate receptor 2-lacking AMPA receptors to extrasynaptic plasma membrane potentiates excitotoxicity. Journal of Neuroscience, 2008, vol. 28, no. 9, pp. 2119—2130. DOI: 10.1523/JNEUROSCI.5159-07.2008
  72. Leonte A., Colzato L.S., Steenbergen L., Hommel B., Akyürek E.G. Supplementation of gamma-aminobutyric acid (GABA) affects temporal, but not spatial visual attention. Brain and Cognition, 2018, vol. 120, pp. 8—16. DOI: 10.1016/j. bandc.2017.11.004
  73. Lieberman O., McGuirt A.F., Tang G., Sulzer D. Roles for neuronal and microglial autophagy in synaptic pruning during development. Neurobiology of Disease, 2019, vol. 122, pp. 49—63. DOI: 10.1016/j.nbd.2018.04.017
  74. Lingford-Hughes A. et al. Imaging the GABA-benzodiazepine receptor subtype containing the α5-subunit in vivo with [11C] Ro15 4513 positron emission tomography. Journal of Cerebral Blood  Flow  & Metabolism, 2002, vol. 22, no. 7,  pp. 878—889. DOI: 10.1097/00004647-200207000-00013
  75. Liu A., Zhou W., Qu L., He F., Wang H., Wang Y., Cai C., Li X., Zhou W., Wang M. Altered Urinary Amino Acids in Children With Autism Spectrum Disorders. Frontiers in Cellular Neuroscience, 2019, vol. 13, p. 7. DOI: 10.3389/fncel.2019.00007
  76. Lu J.-C. et al. GABAA Receptor-Mediated Tonic Depolarization in Developing Neural Circuits. Molecular neurobiology, 2014, vol. 49, no. 2, pp. 702—723. DOI: 10.1007/s12035-013-8548-x
  77. MacDermott A.B., Mayer M.L., Westbrook G.L., Smith S.J., Barker J.L. NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature, 1986, vol. 321, no. 6069, pp. 519—522. DOI: 10.1038/321519a0
  78. MacFabe D.F. et al. Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behavioural brain research, 2007, vol. 176, no. 1, pp. 149—169.  DOI: 10.1016/j.bbr.2006.07.025
  79. Martin L.J. et al. α5GABAA receptor activity sets the threshold for long-term potentiation and constrains hippocampus- dependentmemory.JournalofNeuroscience,2010,vol.30,no.15,pp.5269—5282.DOI:10.1523/JNEUROSCI.4209-09.2010
  80. Mazzone G.L., Nistri A. Modulation of extrasynaptic GABAergic receptor activity influences glutamate release and neuronal survival following excitotoxic damage to mouse spinal cord neurons. Neurochemistry International, 2019, vol. 128, pp. 175—185. DOI: 10.1016/j.neuint.2019.04.018
  81. Mead J., Ashwood P. Evidence supporting an altered immune response in ASD. Immunology Letters, 2015, vol. 163, no. 1, pp. 49—55. DOI: 10.1016/j.imlet.2014.11.006
  82. Meguid N.A., Hashish A.F., Anwar M., Sidhom G. Reduced serum levels of 25-hydroxy and 1, 25-dihydroxy vitamin D in Egyptian children with autism. The Journal of Alternative and Complementary Medicine, 2010, vol. 16, no. 6, pp. 641—645. DOI: 10.1089/acm.2009.0349
  83. Mehta A., Prabhakar M., Kumar P., Deshmukh R., Sharma P.L. Excitotoxicity: bridge to various triggers in neurodegenerative disorders. European journal of pharmacology, 2013, vol. 698, no. 1-3, pp. 6—18. DOI: 10.1016/j.ejphar.2012.10.032
  84. Merner N.D. et al. Regulatory domain or CpG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia. Frontiers in cellular neuroscience, 2015, vol. 9, p. 386. DOI: 10.3389/fncel.2015.00386
  85. Mesbah-Oskui L. et al. Reduced expression of α5GABAA receptors elicits autism-like alterations in EEG patterns and sleep-wake behavior. Neurotoxicology and teratology, 2017, vol. 61, pp. 115—122. DOI: 10.1016/
  86. Moreno-De-Luca D. et al. Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts. Molecular psychiatry, 2013, vol. 18, no. 10, pp. 1090—1095. DOI: 10.1038/mp.2012.138
  87. Mostafa G.A., Al-Ayadhi L.Y. Reduced serum concentrations of 25-hydroxy vitamin D in children with autism: relation to autoimmunity. Journal of neuroinflammation, 2012, vol. 9, no. 1, p. 201. DOI: 10.1186/1742-2094-9-201
  88. Mowery T.M. et al. Embryological exposure to valproic acid disrupts morphology of the deep cerebellar nuclei in a sexually dimorphic way. International Journal of Developmental Neuroscience, 2015, vol. 40, no. 1, pp. 15—23. DOI: 10.1016/j. ijdevneu.2014.10.003
  89. Nelson S.B., Valakh V. Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders. Neuron, 2015, vol. 87, no. 4, pp. 684—698. DOI: 10.1016/j.neuron.2015.07.033
  90. Olloquequi J. et al. Excitotoxicity in the pathogenesis of neurological and psychiatric disorders: Therapeutic implications. Journal of Psychopharmacology, 2018, vol. 32, no. 3, pp. 265—275. DOI: 10.1177/0269881118754680
  91. Olsen R.W., Sieghart W. GABAA receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology, 2009, vol. 56, no. 1, pp. 141—148. DOI:  10.1016/j.neuropharm.2008.07.045
  92. Pajarillo E., Rizor A., Lee J., Aschner M., Lee E. The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: potential targets for neurotherapeutics. Neuropharmacology, 2019, vol. 161, article no. 107559. DOI: 10.1016/j.neuropharm.2019.03.002
  93. Pardo C.A., Vargas D.L., Zimmerman A.W. Immunity, neuroglia and neuroinflammation in autism. International review of psychiatry, 2005, vol. 17, no. 6, pp. 485—495. DOI: 10.1080/02646830500381930
  94. Pascual O., Ben Achour S., Rostaing P., Triller A., Bessis A. Microglia activation triggers astrocyte-mediated modulation   of excitatory neurotransmission.  Proceedings the National Academy of Sciences of the United States of America, 2012, vol. 109, no. 4, pp. E197—E205. DOI: 10.1073/pnas.1111098109
  95. Patel D., Kharkar P.S., Nandave M. Emerging roles of system x - anti-porter and its inhibition in CNS disorders. Molecular membrane biology, 2015, vol. 32, no. 4, pp. 89—116. DOI: 10.3109/09687688.2015.1096972
  96. Pessione E. Lactic acid bacteria contribution to gut microbiota complexity: lights and shadows. Frontiers in cellular and infection microbiology, 2012, vol. 2, p. 86. DOI: 10.3389/fcimb.2012.00086
  97. Pokusaeva   K.   et   al.   GABA-producing  Bifidobacterium  dentium  modulates  visceral  sensitivity  in  the   intestine. Neurogastroenterology & Motility, 2017, vol. 29, no. 1, article no. e12904. DOI: 10.1111/nmo.12904
  98. Raimondo J.V., Richards B.A., Woodin M.A. Neuronal chloride and excitability — the big impact of small changes. Current opinion in neurobiology, 2017, vol. 43, pp. 35—42. DOI: 10.1016/j.conb.2016.11.012
  99. Reuter E., Tafelski S., Thieme K. et al. Die Behandlung des Fibromyalgiesyndroms mit Gamma-Hydroxybuttersäure: Eine randomisierte, kontrollierte Studie [Treatment of fibromyalgia syndrome with gamma-hydroxybutyrate: A randomized controlled study] [published correction appears in: Der Schmerz, 2017, vol. 31, no. 4, pp. 407—412]. Der Schmerz [The pain], 2017, vol. 31, no. 2, 149—158. DOI: 10.1007/s00482-016-0166-x
  100. Rivero-Segura N. et al. Prolactin prevents mitochondrial dysfunction induced by glutamate excitotoxicity in hippocampal neurons. Neuroscience letters, 2019, vol. 701, pp. 58—64. DOI: 10.1016/j.neulet.2019.02.027
  101. Robertson  A.E.,  David  R.S.R.  The sensory experiences of adults with autism spectrum disorder: A qualitative analysis. Perception, 2015, vol. 44, no. 5, pp. 569—586. DOI: 10.1068/p7833
  102. Rojas D.C. The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. Journal of Neural Transmission, 2014, vol. 121, no. 8, pp. 891—905. DOI: 10.1007/s00702-014-1216-0
  103. Rowley N.M., Madsen K.K., Schousboe A., Steve White H. Glutamate and GABA synthesis, release, transport and metabolism as targets for seizure control. Neurochemistry International, 2012, vol. 61, no. 4, pp. 546—558. DOI: 10.1016/j. neuint.2012.02.013
  104. Rubenstein J.L., Merzenich M.M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes, Brain and Behavior, 2003, vol. 2, no. 5, pp. 255—267. DOI: 10.1034/j.1601-183x.2003.00037.x
  105. Saad K. et al. Vitamin D status in autism spectrum disorders and the efficacy of vitamin D supplementation in autistic children. Nutritional neuroscience, 2016, vol. 19, no. 8, pp. 346—351. DOI: 10.1179/1476830515Y.0000000019
  106. Saleem T.H., Shehata G.A., Toghan R. et al. Assessments of Amino Acids, Ammonia and Oxidative Stress Among Cohort of Egyptian Autistic Children: Correlations with Electroencephalogram and Disease Severity [correction published in: Neuropsychiatric Disease and Treatment, 2020, vol. 16, p. 325]. Neuropsychiatric Disease and Treatment, 2020, vol. 16, pp. 11—24. DOI: 10.2147/NDT.S233105
  107. Sano C. History of glutamate production. The American journal of clinical nutrition, 2009, vol. 90, no. 3, pp. 728S—732S. DOI: 10.3945/ajcn.2009.27462F
  108. Schroer R.J. et al. Autism and maternally derived aberrations of chromosome 15q. American journal of medical genetics, 1998, vol. 76, no. 4, pp. 327—336. DOI: 10.1002/(SICI)1096-8628(19980401)76:4<327::AID-AJMG8>3.0.CO;2-M
  109. Sgadò P. et al. Loss of GABAergic neurons in the hippocampus and cerebral cortex of Engrailed-2 null mutant mice: implications for autism spectrum disorders. Experimental neurology, 2013, vol. 247, pp. 496—505. DOI: 10.1016/j. expneurol.2013.01.021
  110. Shao Y. et al. Fine mapping of autistic disorder to chromosome 15q11-q13 by use of phenotypic subtypes. The American Journal of Human Genetics, 2003, vol. 72, no. 3, pp. 539—548. DOI: 10.1086/367846
  111. Shimmura C. et al. Enzymes in the glutamate-glutamine cycle in the anterior cingulate cortex in postmortem brain of subjects with autism. Molecular Autism, 2013, vol. 4, no. 1, p. 6. DOI: 10.1186/2040-2392-4-6
  112. Sibson N.R. et al. In vivo 13C NMR measurements of cerebral glutamine synthesis as evidence for glutamate—glutamine cycling. Proceedings of the National Academy of Sciences of the United States of America, 1997, vol. 94, no. 6, pp. 2699— 2704.  DOI: 10.1073/pnas.94.6.2699
  113. Smaga I. et al. Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part Depression, anxiety, schizophrenia and autism. Pharmacological Reports, 2015, vol. 67, no. 3, pp. 569—580. DOI: 10.1016/j.pharep.2014.12.015
  114. Smidkova M. et al. Screening of Novel 3α5β-Neurosteroids for Neuroprotective Activity against Glutamate-or NMDA- Induced Excitotoxicity. The Journal of steroid biochemistry and molecular biology, 2019, vol. 189, pp. 195—203. DOI: 10.1016/j.jsbmb.2019.03.007
  115. Soni N., Reddy B.V.K., Kumar P. GLT-1 transporter: an effective pharmacological target for various neurological disorders. Pharmacology, Biochemistry and Behavior, 2014, vol. 127, pp. 70—81. DOI: 10.1016/j.pbb.2014.10.001
  116. Tanous C., Gori A., Rijnen L., Chambellon E., Yvon M. Pathways for α-ketoglutarate formation by Lactococcus lactis and their role in amino acid catabolism. International Dairy Journal, 2005, vol. 15, no. 6-9, pp. 759—770. DOI: 10.1016/j. idairyj.2004.09.011
  117. Tebartz van Elst L. et al. Disturbed cingulate glutamate metabolism in adults with high-functioning autism spectrum disorder: evidence in support of the excitatory/inhibitory imbalance hypothesis. Molecular Psychiatry, 2014, vol. 19, no. 12, pp. 1314—1325. DOI: 10.1038/mp.2014.62
  118. Torrez V.R. et al. Memantine mediates astrocytic activity in response to excitotoxicity induced by PP2A inhibition. Neuroscience letters, 2019, vol. 696, pp. 179—183. DOI: 10.1016/j.neulet.2018.12.034
  119. Tyzio R. et al. Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science, 2016, vol. 314, no. 5806, pp. 1788—1792. DOI: 10.1126/science.1133212
  120. Tyzio R. et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science, 2014, vol. 343, no. 6171, pp. 675—679. DOI: 10.1126/science.1247190
  121. Uğur Ç., Gürkan C.K. Serum vitamin D and folate levels in children with autism spectrum disorders. Research in Autism Spectrum Disorders, 2014, vol. 8, no. 12, pp. 1641—1647. DOI: 10.1016/j.rasd.2014.09.002
  122. Vargas D.L., Nascimbene C., Krishnan C., Zimmerman A.W., Pardo C.A. Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals of Neurology, 2005, vol. 57, no. 1, pp. 67—81. DOI: 10.1002/ana.20315
  123. Varman D., Soria-Ortíz M.B., Martínez-Torres A., Reyes-Haro D. GABAρ3 expression in lobule Xof the cerebellum is reduced in the valproate model of autism. Neuroscience letters, 2018, vol. 687, pp. 158—163. DOI: 10.1016/j.neulet.2018.09.042
  124. Vesce S., Rossi D., Brambilla L., Volterra A. Glutamate release from astrocytes in physiological conditions and in neurodegenerative disorders characterized by neuroinflammation. International review of neurobiology, 2007, vol. 82, pp. 57—71. DOI: 10.1016/S0074-7742(07)82003-4
  125. Vinkhuyzen A.A. et al. Gestational vitamin D deficiency and autism-related traits: the Generation R Study. Molecular psychiatry, 2018, vol. 23, no. 2, pp. 240—246. DOI: 10.1038/mp.2016.213
  126. Wakefield A.J. et al. Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands. Alimentary Pharmacology & Therapeutics, 2002, vol. 16, no. 4, pp. 663—674. DOI: 10.1046/j.1365-2036.2002.01206.x
  127. Whitney E., et al. Cerebellar Purkinje cells are reduced in a subpopulation of autistic brains: a stereological experiment using calbindin-D28k. Cerebellum. 2008;7(3):406-416. doi:10.1007/s12311-008-0043-y
  128. Yip J., Soghomonian J.J., Blatt G.J. Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta neuropathologica, 2007, vol. 113, no. 5, pp. 559—568. DOI: 10.1007/s00401-006-0176-3
  129. Yizhar O. et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature, 2011, vol. 477, no. 7363, pp. 171—178. DOI: 10.1038/nature10360
  130. Zareian M., Ebrahimpour A., Mohammed A.K.S., Saari N. Modeling of glutamic acid production by Lactobacillus plantarum MNZ. Electronic Journal of Biotechnology, 2013, vol. 16, no. 4, p. 1—16. DOI: 10.2225/vol16-issue4-fulltext-10
  131. Zurek A.A. et al. α5GABAA receptor deficiency causes autism-like behaviors. Annals of clinical and translational neurology, 2016, vol. 3, no. 5, pp. 392—398. DOI: 10.1002/acn3.303

Information About the Authors

Afaf El-Ansary, PhD, professor of the Central laboratory, Female Centre for Scientific and Medical Studies, King Saud University, Council for Nutritional and Environmental Medicine (CONEM), Riyadh, Saudi Arabia, ORCID:, e-mail:



Total: 2515
Previous month: 48
Current month: 3


Total: 2123
Previous month: 62
Current month: 6