The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment

Glutamate is the major excitatory neurotransmitter in the brain and may be a key neurotransmitter involved in autism. Literature pertaining to glutamate and autism or related disorders (e.g., Fragile X syndrome) is reviewed in this article. Interest in glutamatergic dysfunction in autism is high due to increasing convergent evidence implicating the system in the disorder from peripheral biomarkers, neuroimaging, protein expression, genetics and animal models. Currently, there are no pharmaceutical interventions approved for autism that address glutamate deficits in the disorder. New treatments related to glutamatergic neurotransmission, however, are emerging. In addition, older glutamate-modulating medications with approved indications for use in other disorders are being investigated for re-tasking as treatments for autism. This review presents evidence in support of glutamate abnormalities in autism and the potential for translation into new treatments for the disorder.

[1]  Stephannie L. Furtak,et al.  Magnetic resonance spectroscopy study of the glutamatergic system in adolescent males with high-functioning autistic disorder: a pilot study at 4T , 2013, European Archives of Psychiatry and Clinical Neuroscience.

[2]  J. Stockman,et al.  Prevalence of Parent-Reported Diagnosis of Autism Spectrum Disorder Among Children in the US, 2007 , 2011 .

[3]  Donald C. Rojas,et al.  Decreased left perisylvian GABA concentration in children with autism and unaffected siblings , 2014, NeuroImage.

[4]  E. Bacchelli,et al.  Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene , 2003, Molecular Psychiatry.

[5]  M. Spence,et al.  A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R , 2004, BMC Medical Genetics.

[6]  Laurent Mottron,et al.  NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[7]  Stephen J. Guter,et al.  A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. , 2001, American journal of human genetics.

[8]  A. Toga,et al.  Elevated Glutamatergic Compounds in Pregenual Anterior Cingulate in Pediatric Autism Spectrum Disorder Demonstrated by 1H MRS and 1H MRSI , 2012, PloS one.

[9]  Stephen J. Guter,et al.  AProspective, Open-Label Trial of Memantine in the Treatment of Cognitive, Behavioral, and Memory Dysfunction in Pervasive Developmental Disorders , 2006 .

[10]  M. Tranfaglia,et al.  Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP , 2005, Neuropharmacology.

[11]  K. Hashimoto Emerging role of glutamate in the pathophysiology of major depressive disorder , 2009, Brain Research Reviews.

[12]  J. Mann,et al.  PET and SPECT tracers for glutamate receptors. , 2013, Drug discovery today.

[13]  Fred H. Gage,et al.  Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice , 1998, Nature.

[14]  M. Cuccaro,et al.  Autism and epilepsy: Historical perspective , 2010, Brain and Development.

[15]  J. Miles Autism spectrum disorders—A genetics review , 2011, Genetics in Medicine.

[16]  T. Hassan,et al.  Blood and Brain Glutamate Levels in Children with Autistic Disorder. , 2013 .

[17]  Kenji Mori,et al.  Non-Invasive Evaluation of the GABAergic/Glutamatergic System in Autistic Patients Observed by MEGA-Editing Proton MR Spectroscopy Using a Clinical 3 Tesla Instrument , 2011, Journal of autism and developmental disorders.

[18]  B. Leventhal,et al.  Family-based association testing of glutamate transporter genes in autism. , 2011, Psychiatric genetics.

[19]  S. Musumeci,et al.  Dysregulation of group-I metabotropic glutamate (mGlu) receptor mediated signalling in disorders associated with Intellectual Disability and Autism , 2014, Neuroscience & Biobehavioral Reviews.

[20]  Yi Zhang,et al.  Sibling recurrence and the genetic epidemiology of autism. , 2010, The American journal of psychiatry.

[21]  S. Whiteside,et al.  A magnetic resonance spectroscopy investigation of obsessive–compulsive disorder and anxiety , 2006, Psychiatry Research: Neuroimaging.

[22]  Christine DeLorenzo,et al.  in vivo Variation in Metabotropic Glutamate Receptor Subtype 5 Binding Using Positron Emission Tomography and [11C]ABP688 , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[23]  R. Gur,et al.  GABAB-mediated rescue of altered excitatory–inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction , 2012, Translational Psychiatry.

[24]  Tanya M. Teslovich,et al.  A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. , 2008, American journal of human genetics.

[25]  E. Martin,et al.  In vivo detection of GABA and glutamate with MEGA‐PRESS: Reproducibility and gender effects , 2011, Journal of magnetic resonance imaging : JMRI.

[26]  Zhen Yan,et al.  Shank3 Deficiency Induces NMDA Receptor Hypofunction via an Actin-Dependent Mechanism , 2013, The Journal of Neuroscience.

[27]  Gregor Hasler,et al.  Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. , 2007, Archives of general psychiatry.

[28]  N. W. Pedigo,et al.  Acamprosate inhibits the binding and neurotoxic effects of trans-ACPD, suggesting a novel site of action at metabotropic glutamate receptors. , 2002, Alcoholism, clinical and experimental research.

[29]  Talakad G. Lohith,et al.  Is metabotropic glutamate receptor 5 upregulated in prefrontal cortex in fragile X syndrome? , 2013, Molecular Autism.

[30]  P. Hagerman The fragile X prevalence paradox , 2008, Journal of Medical Genetics.

[31]  C. Skinner,et al.  Neurexin 1α structural variants associated with autism , 2008, Neuroscience Letters.

[32]  Thomas Bourgeron,et al.  Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism , 2003, Nature Genetics.

[33]  D. Licatalosi,et al.  FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism , 2011, Cell.

[34]  G. Barker,et al.  Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [1H]MRS study , 2013, Translational Psychiatry.

[35]  Z. Talebizadeh,et al.  Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism , 2005, Journal of Medical Genetics.

[36]  Q. Guan,et al.  The Two Different Effects of the Potential Neuroprotective Compound Minocycline on AMPA-Type Glutamate Receptors , 2012, Pharmacology.

[37]  Silvia Bernardi,et al.  In vivo 1H-magnetic resonance spectroscopy study of the attentional networks in autism , 2011, Brain Research.

[38]  D. Gutmann,et al.  Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex , 2008, Annals of neurology.

[39]  G. Carlson Glutamate receptor dysfunction and drug targets across models of autism spectrum disorders , 2012, Pharmacology Biochemistry and Behavior.

[40]  Luke Bloy,et al.  GABA estimation in the brains of children on the autism spectrum: Measurement precision and regional cortical variation , 2014, NeuroImage.

[41]  S. Baron-Cohen,et al.  Task-related functional connectivity in autism spectrum conditions: an EEG study using wavelet transform coherence , 2013, Molecular Autism.

[42]  R C Elston,et al.  Linkage and association to genetic markers. , 1995, Experimental and clinical immunogenetics.

[43]  M. Bear,et al.  STX209 (Arbaclofen) for Autism Spectrum Disorders: An 8-Week Open-Label Study , 2014, Journal of autism and developmental disorders.

[44]  Eileen Daly,et al.  In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism. , 2006, The American journal of psychiatry.

[45]  Dick J. Drost,et al.  Evidence for Cortical Dysfunction in Autism: A Proton Magnetic Resonance Spectroscopic Imaging Study , 2007, Biological Psychiatry.

[46]  David B. Holiday,et al.  Seizures in fragile X syndrome: characteristics and comorbid diagnoses. , 2010, American journal on intellectual and developmental disabilities.

[47]  R. Hagerman,et al.  TARGETED TREATMENTS IN AUTISM AND FRAGILE X SYNDROME. , 2012, Research in autism spectrum disorders.

[48]  D. Pinto,et al.  Rare deletions at the neurexin 3 locus in autism spectrum disorder. , 2012, American journal of human genetics.

[49]  Mark F. Bear,et al.  Correction of Fragile X Syndrome in Mice , 2007, Neuron.

[50]  B. Christie,et al.  NMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult Fmr1 knockout mice , 2012, Hippocampus.

[51]  C. McDougle,et al.  Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome , 2013, Psychopharmacology.

[52]  Adam G. Carter,et al.  GABAB receptor modulation of synaptic function , 2011, Current Opinion in Neurobiology.

[53]  A. Kolevzon,et al.  Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency , 2013, Molecular Autism.

[54]  Mira Park,et al.  Family based association of GRIN2A and GRIN2B with Korean autism spectrum disorders , 2012, Neuroscience Letters.

[55]  N. Rinehart,et al.  Autism and ADHD: How far have we come in the comorbidity debate? , 2011, Neuroscience & Biobehavioral Reviews.

[56]  Henry Markram,et al.  Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid , 2007, Proceedings of the National Academy of Sciences.

[57]  J. Storm-Mathisen,et al.  Down‐regulation of Glial Glutamate Transporters after Glutamatergic Denervation in the Rat Brain , 1995, The European journal of neuroscience.

[58]  D. Geschwind,et al.  Autism spectrum disorders: developmental disconnection syndromes , 2007, Current Opinion in Neurobiology.

[59]  T. Struffert,et al.  Multi-voxel magnetic resonance spectroscopy at 3T in patients with idiopathic generalised epilepsy , 2010, Seizure.

[60]  T. Bourgeron,et al.  Linkage and association of the glutamate receptor 6 gene with autism , 2002, Molecular Psychiatry.

[61]  K. Phan,et al.  Anterior cingulate neurochemistry in social anxiety disorder: 1H-MRS at 4 Tesla , 2005, Neuroreport.

[62]  M. Mizuguchi,et al.  Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex , 2012, Nature Communications.

[63]  K. Strauch,et al.  No evidence for involvement of genetic variants in the X‐linked neuroligin genes NLGN3 and NLGN4X in probands with autism spectrum disorder on high functioning level , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[64]  J. Buxbaum,et al.  Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay , 2013, Molecular Autism.

[65]  Albert David,et al.  X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. , 2004, American journal of human genetics.

[66]  L. DeLisi,et al.  Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia , 2011, Translational Psychiatry.

[67]  Lisa Blaskey,et al.  MEG detection of delayed auditory evoked responses in autism spectrum disorders: towards an imaging biomarker for autism , 2010, Autism research : official journal of the International Society for Autism Research.

[68]  L. Soorya,et al.  Metabolic mapping of deep brain structures and associations with symptomatology in autism spectrum disorders. , 2014, Research in autism spectrum disorders.

[69]  Christian R Marshall,et al.  Contribution of SHANK3 mutations to autism spectrum disorder. , 2007, American journal of human genetics.

[70]  M. Carlsson,et al.  Hypothesis: Is infantile autism a hypoglutamatergic disorder? Relevance of glutamate – serotonin interactions for pharmacotherapy , 1998, Journal of Neural Transmission.

[71]  Peter Teale,et al.  BMC Psychiatry BioMed Central Research article Use of antipsychotics and benzodiazepines in patients with psychiatric emergencies: Results of an observational trial , 2008 .

[72]  P. Hagerman,et al.  Autism profiles of males with fragile X syndrome. , 2008, American journal of mental retardation : AJMR.

[73]  K. J. Parker,et al.  Distinct Plasma Profile of Polar Neutral Amino Acids, Leucine, and Glutamate in Children with Autism Spectrum Disorders , 2011, Journal of Autism and Developmental Disorders.

[74]  Mark F. Bear,et al.  Altered synaptic plasticity in a mouse model of fragile X mental retardation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[75]  G. Blatt,et al.  Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications , 2007, Acta Neuropathologica.

[76]  M. Bear,et al.  Chronic Pharmacological mGlu5 Inhibition Corrects Fragile X in Adult Mice , 2012, Neuron.

[77]  M. Bear,et al.  Effects of STX209 (Arbaclofen) on Neurobehavioral Function in Children and Adults with Fragile X Syndrome: A Randomized, Controlled, Phase 2 Trial , 2012, Science Translational Medicine.

[78]  S. Spence,et al.  A genomewide screen of 345 families for autism-susceptibility loci. , 2003, American journal of human genetics.

[79]  B. Christie,et al.  Rescue of NMDAR-dependent synaptic plasticity in Fmr1 knock-out mice. , 2015, Cerebral cortex.

[80]  Stephen J. Guter,et al.  A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders. , 2006, Journal of child and adolescent psychopharmacology.

[81]  C. McDougle,et al.  An open-label naturalistic pilot study of acamprosate in youth with autistic disorder. , 2011, Journal of child and adolescent psychopharmacology.

[82]  M. Mohammadi,et al.  Memantine as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial. , 2013, The international journal of neuropsychopharmacology.

[83]  Chao Lu,et al.  Retrospective study , 2016, Medicine.

[84]  Geraldine Dawson,et al.  Atypical developmental patterns of brain chemistry in children with autism spectrum disorder. , 2013, JAMA psychiatry.

[85]  D. Rojas,et al.  Increased Glutamate Concentration in the Auditory Cortex of Persons With Autism and First‐Degree Relatives: A 1H‐MRS Study , 2013, Autism research : official journal of the International Society for Autism Research.

[86]  A. Fisahn,et al.  Kainate receptors and rhythmic activity in neuronal networks: hippocampal gamma oscillations as a tool , 2005, The Journal of physiology.

[87]  T. Kemper,et al.  Density and Distribution of Hippocampal Neurotransmitter Receptors in Autism: An Autoradiographic Study , 2001, Journal of autism and developmental disorders.

[88]  T. Südhof,et al.  Neuroligin-1 Deletion Results in Impaired Spatial Memory and Increased Repetitive Behavior , 2010, The Journal of Neuroscience.

[89]  P. Conn,et al.  Metabotropic glutamate receptors: physiology, pharmacology, and disease. , 2010, Annual review of pharmacology and toxicology.

[90]  S. Bryson,et al.  Recurrence Risk for Autism Spectrum Disorders: A Baby Siblings Research Consortium Study , 2011, Pediatrics.

[91]  Yiping Shen,et al.  Deletions of NRXN1 (Neurexin-1) Predispose to a Wide Spectrum of Developmental Disorders , 2010, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[92]  M. Sheng The postsynaptic NMDA-receptor--PSD-95 signaling complex in excitatory synapses of the brain. , 2001, Journal of cell science.

[93]  B. Cormand,et al.  Rare variants analysis of neurexin-1&bgr; in autism reveals a novel start codon mutation affecting protein levels at synapses , 2013, Psychiatric genetics.

[94]  A. Ghanizadeh Increased Glutamate and Homocysteine and Decreased Glutamine Levels in Autism: A Review and Strategies for Future Studies of Amino Acids in Autism , 2013, Disease markers.

[95]  S. Rogers,et al.  The Behavioral Phenotype in Fragile X: Symptoms of Autism in Very Young Children with Fragile X Syndrome, Idiopathic Autism, and Other Developmental Disorders , 2001, Journal of developmental and behavioral pediatrics : JDBP.

[96]  C. McDougle,et al.  Open-Label Memantine in Fragile X Syndrome , 2009, Journal of autism and developmental disorders.

[97]  H. McDermid,et al.  The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome) , 2011, Molecular Syndromology.

[98]  D. Ethell,et al.  Open-label add-on treatment trial of minocycline in fragile X syndrome , 2010, BMC neurology.

[99]  A. Bailey,et al.  Autism as a strongly genetic disorder: evidence from a British twin study , 1995, Psychological Medicine.

[100]  Hongyan Wang,et al.  Lack of Association between NLGN3, NLGN4, SHANK2 and SHANK3 Gene Variants and Autism Spectrum Disorder in a Chinese Population , 2013, PloS one.

[101]  J. Brunso-Bechtold,et al.  Differential effects of aging and insulin-like growth factor-1 on synapses in CA1 of rat hippocampus. , 2005, Cerebral cortex.

[102]  M. Reiff Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. , 2001 .

[103]  L. Schieve,et al.  Prevalence of Parent-Reported Diagnosis of Autism Spectrum Disorder Among Children in the US, 2007 , 2009, Pediatrics.

[104]  Yosuke Kameno,et al.  Alteration of Plasma Glutamate and Glutamine Levels in Children with High-Functioning Autism , 2011, PloS one.

[105]  D. Nguyen,et al.  A pilot open label, single dose trial of fenobam in adults with fragile X syndrome , 2009, Journal of Medical Genetics.

[106]  Yoshio Minabe,et al.  Increased serum levels of glutamate in adult patients with autism , 2006, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[107]  P. Turnpenny,et al.  Characteristics of fetal anticonvulsant syndrome associated autistic disorder. , 2005, Developmental medicine and child neurology.

[108]  J. Swann,et al.  Multiple Roles for Mammalian Target of Rapamycin Signaling in Both Glutamatergic and GABAergic Synaptic Transmission , 2012, The Journal of Neuroscience.

[109]  C. McDougle,et al.  Brief Report: Acamprosate in Fragile X Syndrome , 2010, Journal of autism and developmental disorders.

[110]  Kenny Q. Ye,et al.  Strong Association of De Novo Copy Number Mutations with Autism , 2007, Science.

[111]  K. McBride,et al.  Genetic testing in autism: how much is enough? , 2007, Genetics in Medicine.

[112]  Family‐based association for quantitative traits. , 2014 .

[113]  Aberrant basal ganglia metabolism in fragile X syndrome: a magnetic resonance spectroscopy study , 2013, Journal of Neurodevelopmental Disorders.

[114]  K. Hashimoto,et al.  Enzymes in the glutamate-glutamine cycle in the anterior cingulate cortex in postmortem brain of subjects with autism , 2013, Molecular Autism.

[115]  Jullie W Pan,et al.  Rett Syndrome: 1H Spectroscopic Imaging at 4.1 Tesla , 1999, Journal of child neurology.

[116]  L. Borjas,et al.  Plasma excitatory amino acids in autism. , 1996, Investigacion clinica.

[117]  K. Davis,et al.  Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. , 2004, The American journal of psychiatry.

[118]  Axel Benner,et al.  Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. , 2001, Human molecular genetics.

[119]  A. Williamson,et al.  Overexpression of GluR6 in Rat Hippocampus Produces Seizures and Spontaneous Nonsynaptic Bursting in Vitro , 2000, Neurobiology of Disease.

[120]  Dai Zhang,et al.  Family‐based association study between autism and glutamate receptor 6 gene in Chinese Han trios , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[121]  J. Jordán,et al.  Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca2+ signalling in hippocampal neurons , 2007, The European journal of neuroscience.

[122]  M. Fitzgerald,et al.  Plasma Amino Acid Levels in Children with Autism and Their Families , 2003, Journal of autism and developmental disorders.

[123]  Stephen T Warren,et al.  Molecular mechanisms of fragile X syndrome: a twenty-year perspective. , 2012, Annual review of pathology.

[124]  C. McDougle,et al.  A retrospective study of memantine in children and adolescents with pervasive developmental disorders , 2007, Psychopharmacology.

[125]  Alcino J. Silva,et al.  Rapamycin for treating Tuberous sclerosis and Autism spectrum disorders. , 2011, Trends in molecular medicine.

[126]  M. Cuccaro,et al.  Autism spectrum disorders and epilepsy: Moving towards a comprehensive approach to treatment , 2010, Brain and Development.

[127]  Norbert Schuff,et al.  Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T , 2005, Neurobiology of Aging.

[128]  P. Garcia,et al.  Minocycline- and tetracycline-class antibiotics are protective against partial seizures in vivo , 2012, Epilepsy & Behavior.

[129]  T. Südhof,et al.  Common circuit defect of excitatory-inhibitory balance in mouse models of autism , 2009, Journal of Neurodevelopmental Disorders.

[130]  James H. Eubanks,et al.  Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome , 2006, Neurobiology of Disease.

[131]  R. Citraro,et al.  New AMPA antagonists in epilepsy , 2012, Expert opinion on investigational drugs.

[132]  L. Borjas,et al.  [Clinical heterogeneity of the autistic syndrome: a study of 60 families]. , 1992, Investigacion clinica.

[133]  Bonnie M. MacNeil,et al.  Anxiety in Children and Adolescents with Autism Spectrum Disorders. , 2009 .

[134]  S. Rivera,et al.  A Randomized Double-Blind, Placebo-Controlled Trial of Minocycline in Children and Adolescents with Fragile X Syndrome , 2013, Journal of developmental and behavioral pediatrics : JDBP.

[135]  M. Waters,et al.  of Insulin-Like Growth , 1993 .

[136]  M. Rutter,et al.  Genetics and child psychiatry: II Empirical research findings. , 1999, Journal of child psychology and psychiatry, and allied disciplines.

[137]  J. Walecki,et al.  Proton Magnetic Resonance Spectroscopy Study of Brain Metabolite Changes after Antipsychotic Treatment , 2011, Pharmacopsychiatry.

[138]  R. Martínez-Leal,et al.  Mutations affecting synaptic levels of neurexin-1β in autism and mental retardation , 2012, Neurobiology of Disease.

[139]  S. Schachter,et al.  The NMDA receptor complex as a therapeutic target in epilepsy: a review , 2011, Epilepsy & Behavior.

[140]  J. Edgar,et al.  Validating γ Oscillations and Delayed Auditory Responses as Translational Biomarkers of Autism , 2010, Biological Psychiatry.

[141]  Thomas Bourgeron,et al.  Mapping autism risk loci using genetic linkage and chromosomal rearrangements , 2007, Nature Genetics.

[142]  K. Grotemeyer,et al.  Serotonin and amino acid content in platelets of autistic children , 1993, Acta psychiatrica Scandinavica.

[143]  S. Fatemi,et al.  Metabotropic Glutamate Receptor 5 Upregulation in Children with Autism is Associated with Underexpression of Both Fragile X Mental Retardation Protein and GABAA Receptor Beta 3 in Adults with Autism , 2011, Anatomical record.

[144]  F. Serajee,et al.  The metabotropic glutamate receptor 8 gene at 7q31: partial duplication and possible association with autism , 2003, Journal of medical genetics.

[145]  Janice Branson,et al.  Epigenetic Modification of the FMR1 Gene in Fragile X Syndrome Is Associated with Differential Response to the mGluR5 Antagonist AFQ056 , 2011, Science Translational Medicine.

[146]  H. Niederhofer Glutamate antagonists seem to be slightly effective in psychopharmacologic treatment of autism. , 2007, Journal of clinical psychopharmacology.

[147]  G. Arbanas Diagnostic and Statistical Manual of Mental Disorders (DSM-5) , 2015 .

[148]  David R. Hampson,et al.  Increased GABAB Receptor-Mediated Signaling Reduces the Susceptibility of Fragile X Knockout Mice to Audiogenic Seizures , 2009, Molecular Pharmacology.

[149]  C. Shepherd,et al.  A prevalence study of autism in tuberous sclerosis , 1993, Journal of autism and developmental disorders.

[150]  S. Kennedy,et al.  Novel therapeutic targets in depression: Minocycline as a candidate treatment , 2012, Behavioural Brain Research.

[151]  A. Hardan,et al.  Underutilization of Genetics Services for Autism: The Importance of Parental Awareness and Provider Recommendation , 2012, Journal of Genetic Counseling.

[152]  Carlos A. Zarate,et al.  Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders , 2008, Nature Reviews Drug Discovery.

[153]  M. Chez,et al.  Memantine as Adjunctive Therapy in Children Diagnosed With Autistic Spectrum Disorders: An Observation of Initial Clinical Response and Maintenance Tolerability , 2007, Journal of child neurology.

[154]  Janet E. Lainhart,et al.  Overrepresentation of mood and anxiety disorders in adults with autism and their first‐degree relatives: what does it mean? , 2008, Autism research : official journal of the International Society for Autism Research.

[155]  Mark F Bear,et al.  The mGluR theory of fragile X mental retardation , 2004, Trends in Neurosciences.

[156]  J. Pevsner,et al.  Postmortem brain abnormalities of the glutamate neurotransmitter system in autism , 2001, Neurology.

[157]  J. Mowrey,et al.  Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. , 2009, American journal of human genetics.

[158]  Ryszard Przewłocki,et al.  Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Animal Model of Autism , 2005, Neuropsychopharmacology.

[159]  L. Lee,et al.  A pilot open-label trial of minocycline in patients with autism and regressive features , 2013, Journal of Neurodevelopmental Disorders.

[160]  Sheik Hosenbocus,et al.  Memantine: a review of possible uses in child and adolescent psychiatry. , 2013, Journal of the Canadian Academy of Child and Adolescent Psychiatry = Journal de l'Academie canadienne de psychiatrie de l'enfant et de l'adolescent.

[161]  R. S. Jones The NMDA receptor Edited by J. C. Watkins and G. L. Collinridge. Oxford University Press, New York (1990) 242 pp. £45.00 , 1991, Neuroscience.

[162]  C. Betancur,et al.  Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting , 2011, Brain Research.

[163]  D. Toncheva,et al.  Analysis of the genes encoding neuroligins NLGN3 and NLGN4 in Bulgarian patients with autism. , 2012, Genetic counseling.

[164]  S. Schulz,et al.  Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices , 2002, Biological Psychiatry.