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

Aldred S, Moore KM, Fitzgerald M, Waring RH (2003) Plasma amino acid levels in children with autism and their families. J Autism Dev Disord 33:93–97PubMed

American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association, Washington

Arking DE, Cutler DJ, Brune CW et al (2008) A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet 82:160–164. doi:10.1016/j.ajhg.2007.09.015 PubMedPubMedCentral

Asaka Y, Jugloff DGM, Zhang L et al (2006) Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol Dis 21:217–227. doi:10.1016/j.nbd.2005.07.005 PubMed

Autism Genome Project Consortium, Szatmari P, Paterson AD et al (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39:319–328. doi:10.1038/ng1985 PubMed

Avdjieva-Tzavella DM, Todorov TP, Todorova AP et al (2012) Analysis of the genes encoding neuroligins NLGN3 and NLGN4 in Bulgarian patients with autism. Genet Couns 23:505–511PubMed

Bacchelli E, Blasi F, Biondolillo M et al (2003) Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene. Mol Psychiatry 8:916–924. doi:10.1038/sj.mp.4001340 PubMed

Bailey A, Le Couteur A, Gottesman I et al (1995) Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 25:63–77PubMed

Bear MF, Huber KM, Warren ST (2004) The mGluR theory of fragile X mental retardation. Trends Neurosci 27:370–377. doi:10.1016/j.tins.2004.04.009 PubMed

Bejjani A, O’Neill J, Kim JA et al (2012) Elevated glutamatergic compounds in pregenual anterior cingulate in pediatric autism spectrum disorder demonstrated by 1H MRS and 1H MRSI. PLoS One 7:e38786. doi:10.1371/journal.pone.0038786.t004 PubMedPubMedCentral

Bernardi S, Anagnostou E, Shen J et al (2011) In vivo 1H-magnetic resonance spectroscopy study of the attentional networks in autism. Brain Res 1380:198–205. doi:10.1016/j.brainres.2010.12.057 PubMedPubMedCentral

Berry-Kravis E, Hessl D, Coffey S et al (2009) A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. J Med Genet 46:266–271. doi:10.1136/jmg.2008.063701 PubMedPubMedCentral

Berry-Kravis E, Raspa M, Loggin-Hester L et al (2010) Seizures in fragile X syndrome: characteristics and comorbid diagnoses. Am J Intellect Dev Disabil 115:461–472. doi:10.1352/1944-7558-115.6.461 PubMed

Berry-Kravis EM, Hessl D, Rathmell B et al (2012) Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Sci Transl Med 4:152ra127. doi:10.1126/scitranslmed.3004214 PubMed

Betancur C (2011) Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res 1380:42–77. doi:10.1016/j.brainres.2010.11.078 PubMed

Blatt GJ, Fitzgerald CM, Guptill JT et al (2001) Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. J Autism Dev Disord 31:537–543PubMed

Blundell J, Blaiss CA, Etherton MR et al (2010) Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J Neurosci 30:2115–2129. doi:10.1523/JNEUROSCI.4517-09.2010 PubMedPubMedCentral

Bostrom CA, Majaess NM, Morch K et al (2013) Rescue of NMDAR-dependent synaptic plasticity in Fmr1 knock-out mice. Cereb Cortex. doi:10.1093/cercor/bht237 PubMed

Bozdagi O, Tavassoli T, Buxbaum JD (2013) Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay. Mol Autism 4:9. doi:10.1186/2040-2392-4-9 PubMedPubMedCentral

Brown MS, Singel D, Hepburn S, Rojas DC (2013) Increased glutamate concentration in the auditory cortex of persons with autism and first-degree relatives: a 1H-MRS study. Autism Res 6:1–10. doi:10.1002/aur.1260 PubMedPubMedCentral

Bruno JL, Shelly EW, Quintin E-M et al (2013) Aberrant basal ganglia metabolism in fragile X syndrome: a magnetic resonance spectroscopy study. J Neurodevelop Disord 5:20. doi:10.1186/1866-1955-5-20

Camacho-Garcia RJ, Planelles MI, Margalef M et al (2012) Mutations affecting synaptic levels of neurexin-1β in autism and mental retardation. Neurobiol Dis 47:135–143. doi:10.1016/j.nbd.2012.03.031 PubMed

Camacho-Garcia RJ, Hervás A, Toma C et al (2013) Rare variants analysis of neurexin-1β in autism reveals a novel start codon mutation affecting protein levels at synapses. Psychiatr Genet 23:262–266. doi:10.1097/YPG.0000000000000013 PubMed

Carlson GC (2012) Glutamate receptor dysfunction and drug targets across models of autism spectrum disorders. Pharmacol Biochem Behav 100:850–854. doi:10.1016/j.pbb.2011.02.003 PubMedPubMedCentral

Carlsson ML (1998) Hypothesis: is infantile autism a hypoglutamatergic disorder? Relevance of glutamate–serotonin interactions for pharmacotherapy. J Neural Transm 105:525–535PubMed

Chalifoux JR, Carter AG (2011) GABAB receptor modulation of synaptic function. Curr Opin Neurobiol 21:339–344. doi:10.1016/j.conb.2011.02.004 PubMedPubMedCentral

Chez MG, Burton Q, Dowling T et al (2007) Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability. J Child Neurol 22:574–579. doi:10.1177/0883073807302611 PubMed

Ching MSL, Shen Y, Tan W-H et al (2010) Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders. Am J Med Genet B Neuropsychiatr Genet 153B:937–947. doi:10.1002/ajmg.b.31063 PubMedPubMedCentral

Coffee B, Keith K, Albizua I et al (2009) AR TICLEIncidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet 85:503–514. doi:10.1016/j.ajhg.2009.09.007 PubMedPubMedCentral

Constantino JN, Zhang Y, Frazier T et al (2010) Sibling recurrence and the genetic epidemiology of autism. Am J Psychiatry 167:1349–1356. doi:10.1176/appi.ajp.2010.09101470 PubMedPubMedCentral

Corrigan NM, Shaw DWW, Estes AM et al (2013) Atypical developmental patterns of brain chemistry in children with autism spectrum disorder. JAMA Psychiatry 70(9):964–974. doi:10.1001/jamapsychiatry.2013.1388 PubMed

D’Antoni S, Spatuzza M, Bonaccorso CM, et al. (2014) Neurosci Biobehav Rev 1–14. doi: 10.1016/j.neubiorev.2014.02.003 (in press)

Darnell JC, Van Driesche SJ, Zhang C et al (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146:247–261. doi:10.1016/j.cell.2011.06.013 PubMedPubMedCentral

DeLorenzo C, Kumar JSD, Mann JJ, Parsey RV (2011) In vivo variation in metabotropic glutamate receptor subtype 5 binding using positron emission tomography and [11C]ABP688 31:2169–2180. doi: 10.1038/jcbfm.2011.105

DeVito TJ, Drost DJ, Neufeld RWJ et al (2007) Evidence for cortical dysfunction in autism: a proton magnetic resonance spectroscopic imaging study. Biol Psychiatry 61:465–473. doi:10.1016/j.biopsych.2006.07.022 PubMed

Doelken MT, Mennecke A, Stadlbauer A et al (2010) Multi-voxel magnetic resonance spectroscopy at 3 T in patients with idiopathic generalised epilepsy. Seizure Eur J Epilepsy 19:485–492. doi:10.1016/j.seizure.2010.07.005

Dölen G, Osterweil E, Rao BSS et al (2007) Correction of fragile X syndrome in mice. Neuron 56:955–962. doi:10.1016/j.neuron.2007.12.001 PubMedPubMedCentral

Doyle-Thomas KAR, Card D, Soorya LV et al (2014) Metabolic mapping of deep brain structures and associations with symptomatology in autism spectrum disorders. Res Autism Spectr Disord 8:44–51. doi:10.1016/j.rasd.2013.10.003 PubMedPubMedCentral

Duffney LJ, Wei J, Cheng J et al (2013) Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism. J Neurosci 33:15767–15778. doi:10.1523/JNEUROSCI.1175-13.2013 PubMedPubMedCentral

Eadie BD, Cushman J, Kannangara TS et al (2010) NMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult Fmr1 knockout mice. Hippocampus 22:241–254. doi:10.1002/hipo.20890 PubMed

Ehninger D, Silva AJ (2011) Rapamycin for treating tuberous sclerosis and autism spectrum disorders. Trends Mol Med 17:78–87. doi:10.1016/j.molmed.2010.10.002 PubMedPubMedCentral

Erickson CA, Posey DJ, Stigler KA et al (2006) A retrospective study of memantine in children and adolescents with pervasive developmental disorders. Psychopharmacology 191:141–147. doi:10.1007/s00213-006-0518-9 PubMed

Erickson CA, Mullett JE, McDougle CJ (2009) Open-label memantine in fragile X syndrome. J Autism Dev Disord 39:1629–1635. doi:10.1007/s10803-009-0807-3 PubMed

Erickson CA, Mullett JE, McDougle CJ (2010) Brief report: acamprosate in fragile X syndrome. J Autism Dev Disord 40:1412–1416. doi:10.1007/s10803-010-0988-9 PubMed

Erickson CAC, Early MM, Stigler KAK et al (2011) An open-label naturalistic pilot study of acamprosate in youth with autistic disorder. J Child Adolesc Psychopharmacol 21:565–569. doi:10.1089/cap.2011.0034 PubMedPubMedCentral

Erickson CA, Veenstra-Vanderweele JM, Melmed RD et al (2013a) STX209 (Arbaclofen) for autism spectrum disorders: an 8-week open-label study. J Autism Dev Disord 44:958–964. doi:10.1007/s10803-013-1963-z

Erickson CA, Wink LK, Ray B et al (2013b) Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome. Psychopharmacology 228:75–84. doi:10.1007/s00213-013-3022-z PubMed

Fatemi SH (2008) The hyperglutamatergic hypothesis of autism. Prog Neuropsychopharmacol Biol Psychiatry 32:911. doi:10.1016/j.pnpbp.2007.11.004 PubMed

Fatemi SH, Halt AR, Stary JM et al (2002) Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry 52:805–810PubMed

Fatemi SH, Folsom TD, Kneeland RE, Liesch SB (2011) 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. Anat Rec (Hoboken) 294:1635–1645. doi:10.1002/ar.21299

Fisahn A (2005) Kainate receptors and rhythmic activity in neuronal networks: hippocampal gamma oscillations as a tool. J Physiol 562:65–72. doi:10.1113/jphysiol.2004.077388 PubMedPubMedCentral

Gaetz W, Bloy L, Wang DJ et al (2014) GABA estimation in the brains of children on the autism spectrum: Measurement precision and regional cortical variation. NeuroImage 86:1–9. doi:10.1016/j.neuroimage.2013.05.068 PubMed

Gandal MJ, Edgar JC, Ehrlichman RS et al (2010) Validating γ oscillations and delayed auditory responses as translational biomarkers of autism. Biol Psychiatry 68:1100–1106. doi:10.1016/j.biopsych.2010.09.031 PubMed

Gandal MJ, Sisti J, Klook K et al (2012) GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction. Transl Psychiatry 2:e142. doi:10.1038/tp.2012.69 PubMedPubMedCentral

Gargaro BA, Rinehart NJ, Bradshaw JL et al (2011) Autism and ADHD: how far have we come in the comorbidity debate? Neurosci Biobehav Rev 35:1081–1088. doi:10.1016/j.neubiorev.2010.11.002 PubMed

Gauthier J, Bonnel A, St-Onge J et al (2005) NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population. Am J Med Genet B Neuropsychiatr Genet 132B:74–75. doi:10.1002/ajmg.b.30066 PubMed

Geschwind DH, Levitt P (2007) Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol 17:103–111. doi:10.1016/j.conb.2007.01.009 PubMed

Ghaleiha A, Asadabadi M, Mohammadi MR et al (2013) Memantine as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol 16:783–789. doi:10.1017/S1461145712000880 PubMed

Ghanizadeh A (2013) Increased glutamate and homocysteine and decreased glutamine levels in autism: a review and strategies for future studies of amino acids in autism. Dis Markers 35:281–286. doi:10.1016/j.febslet.2012.01.049 PubMedPubMedCentral

Ghasemi M, Schachter SC (2011) The NMDA receptor complex as a therapeutic target in epilepsy: a review. Epilepsy Behav 22:617–640. doi:10.1016/j.yebeh.2011.07.024 PubMed

Gogolla N, Leblanc JJ, Quast KB et al (2009) Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodevelop Disord 1:172–181. doi:10.1007/s11689-009-9023-x

González JC, Egea J, Del Carmen Godino M et al (2007) Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca2+ signalling in hippocampal neurons. Eur J Neurosci 26:2481–2495. doi:10.1111/j.1460-9568.2007.05873.x PubMed

Gürkan CK, Hagerman RJ (2012) Targeted treatments in autism and fragile X syndrome. Res Autism Spectr Disord 6:1311–1320. doi:10.1016/j.rasd.2012.05.007 PubMedPubMedCentral

Hagerman PJ (2008) The fragile X prevalence paradox. J Med Genet 45:498–499. doi:10.1136/jmg.2008.059055 PubMedPubMedCentral

Harada M, Taki MM, Nose A et al (2010) Non-invasive evaluation of the GABAergic/glutamatergic system in autistic patients observed by MEGA-editing proton MR spectroscopy using a clinical 3 Tesla instrument. J Autism Dev Disord 41:447–454. doi:10.1007/s10803-010-1065-0

Harris BR, Prendergast MA, Gibson DA et al (2002) Acamprosate inhibits the binding and neurotoxic effects of trans-ACPD, suggesting a novel site of action at metabotropic glutamate receptors. Alcoholism Clin Exp Res 26:1779–1793. doi:10.1097/01.ALC.0000042011.99580.98

Harris SW, Hessl D, Goodlin-Jones B et al (2008) Autism profiles of males with fragile X syndrome. Am J Ment Retard 113:427–438. doi:10.1352/2008.113:427-438 PubMedPubMedCentral

Hashimoto K (2009) Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res Rev 61:105–123. doi:10.1016/j.brainresrev.2009.05.005 PubMed

Hasler G, van der Veen JW, Tumonis T et al (2007) Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry 64:193–200. doi:10.1001/archpsyc.64.2.193 PubMed

Hassan TH, Abdelrahman HM, Fattah NRA et al (2013) Blood and brain glutamate levels in children with autistic disorder. Res Autism Spectr Disord 7:541–548. doi:10.1016/j.rasd.2012.12.005

Herman GE, Henninger N, Ratliff-Schaub K et al (2007) Genetic testing in autism: how much is enough? Genet Med 9:268–274PubMed

Horder J, Lavender T, Mendez MA, O’Gorman R (2013) Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a 1H MRS study. Transl Psychiatry. doi:10.1038/tp.2013.53 PubMedPubMedCentral

Hosenbocus S, Chahal R (2013) Memantine: a review of possible uses in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry 22:166PubMedPubMedCentral

Huber KM, Gallagher SM, Warren ST, Bear MF (2002) Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci 99:7746–7750. doi:10.1073/pnas.122205699 PubMedPubMedCentral

Hunt A, Shepherd C (1993) A prevalence study of autism in tuberous sclerosis. J Autism Dev Disord 23:323–339PubMed

International Molecular Genetic Study of Autism Consortium (IMGSAC) (2001a) Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. Hum Mol Genet 10:973–982

International Molecular Genetic Study of Autism Consortium (IMGSAC) (2001b) A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 69:570–581. doi:10.1086/323264

Jacob S, Brune CW, Badner JA et al (2011) Family-based association testing of glutamate transporter genes in autism. Psychiatr Genet 21:212–213. doi:10.1097/YPG.0b013e328341a323 PubMedPubMedCentral

Jacquemont S, Curie A, Portes des V et al (2011) Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med 3:64ra1. doi:10.1126/scitranslmed.3001708 PubMed

Jamain S, Betancur C, Quach H et al (2002) Linkage and association of the glutamate receptor 6 gene with autism. Mol Psychiatry 7:302–310. doi:10.1038/sj.mp.4000979 PubMedPubMedCentral

Jamain S, Quach H, Betancur C et al (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 34:27–29. doi:10.1038/ng1136 PubMedPubMedCentral

Jin L-J, Schlesinger F, Guan Q et al (2012) The two different effects of the potential neuroprotective compound minocycline on AMPA-type glutamate receptors. Pharmacology 89:156–162PubMed

Joshi G, Biederman J, Wozniak J et al (2012) Magnetic resonance spectroscopy study of the glutamatergic system in adolescent males with high-functioning autistic disorder: a pilot study at 4T. Eur Arch Psychiatry Clin Neurosci. doi:10.1007/s00406-012-0369-9 PubMed

Kaiser LG, Schuff N, Cashdollar N, Weiner MW (2005) Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T. Neurobiol Aging 26:665–672. doi:10.1016/j.neurobiolaging.2004.07.001 PubMedPubMedCentral

King BH, Wright DM, Handen BL et al (2001) Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. JAAC 40:658–665. doi:10.1097/00004583-200106000-00010

Kogan MD, Blumberg SJ, Schieve LA et al (2009) Prevalence of parent-reported diagnosis of autism spectrum disorder among children in the US, 2007. Pediatrics 124:1395–1403. doi:10.1542/peds.2009-1522 PubMed

Laumonnier F, Bonnet-Brilhault F, Gomot M (2004) X-Linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the Neuroligin family. Am J Hum Genet 74(3):552–557

Leigh MJS, Nguyen DV, Mu Y et al (2013) A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile x syndrome. J Dev Behav Pediatr 34:147–155. doi:10.1097/DBP.0b013e318287cd17 PubMedPubMedCentral

Levy LM, Lehre KP, Walaas SI et al (1995) Down-regulation of glial glutamate transporters after glutamatergic denervation in the rat brain. Eur J Neurosci 7:2036–2041PubMed

Liu Y, Du Y, Liu W et al (2013) Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population. PLoS One 8:e56639. doi:10.1371/journal.pone.0056639 PubMedPubMedCentral

Lohith TG, Osterweil EK, Fujita M et al (2013) Is metabotropic glutamate receptor 5 upregulated in prefrontal cortex in fragile X syndrome? Mol Autism 4:1. doi:10.1186/2040-2392-4-15

Majo VJ, Prabhakaran J, Mann JJ, Kumar JSD (2013) PET and SPECT tracers for glutamate receptors. Drug Discov Today 18:173–184. doi:10.1016/j.drudis.2012.10.004 PubMed

Mazefsky CA, Folstein SE, Lainhart JE (2008) Overrepresentation of mood and anxiety disorders in adults with autism and their first-degree relatives: what does it mean? Autism Res 1:193–197. doi:10.1002/aur.23 PubMedPubMedCentral

Michalon A, Sidorov M, Ballard TM et al (2012) Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 74:49–56. doi:10.1016/j.neuron.2012.03.009 PubMed

Miles JH (2011) Autism spectrum disorders—a genetics review. Genet Med 13:278–294. doi:10.1097/GIM.0b013e3181ff67ba PubMed

Moessner R, Marshall CR, Sutcliffe JS et al (2007) Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet 81:1289–1297. doi:10.1086/522590 PubMedPubMedCentral

Moreno H, Borjas L, Arrieta A, Saez L (1992) Clinical heterogeneity of the autistic syndrome: a study of 60 families. Invest Clin 33(1):13–31

Moreno-Fuenmayor H, Borjas L, Arrieta A et al (1996) Plasma excitatory amino acids in autism. Invest Clin 37:113–128PubMed

Mulle C, Sailer A, Pérez-Otaño I et al (1998) Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice. Nature 392:601–605. doi:10.1038/33408 PubMed

Niederhofer H (2007) Glutamate antagonists seem to be slightly effective in psychopharmacologic treatment of autism. J Clin Psychopharmacol 27:317–318. doi:10.1097/01.jcp.0000270082.30500.69 PubMed

Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50:295–322. doi:10.1146/annurev.pharmtox.011008.145533 PubMedPubMedCentral

O’’orman RL, Michels L, Edden RA et al (2011) In vivo detection of GABA and glutamate with MEGA-PRESS: reproducibility and gender effects. J Magn Reson Imaging 33:1262–1267. doi:10.1002/jmri.22520

Owley T, Salt J, Guter S et al (2006) A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders. J Child Adolesc Psychopharmacol 16:517–524. doi:10.1089/cap.2006.16.517 PubMed

Ozonoff S, Young GS, Carter A et al (2011) Recurrence risk for autism spectrum disorders: a baby siblings research consortium study. Pediatrics 128:488–495. doi:10.1542/peds.2010-2825

Pacey LKK, Heximer SP, Hampson DR (2009) Increased GABAB receptor-mediated signaling reduces the susceptibility of fragile X knockout mice to audiogenic seizures. Mol Pharmacol 76:18–24. doi:10.1124/mol.109.056127 PubMed

Page LA, Daly E, Schmitz N et al (2006) In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism. Am J Psychiatry 163:2189–2192. doi:10.1176/appi.ajp.163.12.2189 PubMed

Pan JW, Lane JB, Hetherington H, Percy AK (1999) Rett syndrome: 1H spectroscopic imaging at 4.1 Tesla. J Child Neurol 14:524–528PubMed

Pardo CA, Buckley A, Thurm A et al (2013) A pilot open-label trial of minocycline in patients with autism and regressive features. J Neurodevelop Disord 5:9. doi:10.1186/1866-1955-5-9

Paribello C, Tao L, Folino A et al (2010) Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurology 10:91. doi:10.1186/1471-2377-10-91 PubMedPubMedCentral

Phan KL, Fitzgerald DA, Cortese BM et al (2005) Anterior cingulate neurochemistry in social anxiety disorder: 1H-MRS at 4 Tesla. NeuroReport 16:183–186PubMed

Phelan K, McDermid HE (2012) The 22q13.3 deletion syndrome (Phelan-McDermid syndrome). Mol Syndromol 2:186–201PubMedPubMedCentral

Purcell AE, Jeon OH, Zimmerman AW et al (2001) Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology 57:1618–1628PubMed

Ramanathan S, Woodroffe A, Flodman PL et al (2004) 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. BMC Med Genet 5:10. doi:10.1186/1471-2350-5-10 PubMedPubMedCentral

Ramoz N, Reichert JG, Smith CJ et al (2004) Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiatry 161:662–669. doi:10.1176/appi.ajp.161.4.662 PubMed

Rasalam AD, Hailey H, Williams JHG et al (2005) Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Dev Med Child Neurol 47:551–555PubMed

Rinaldi T, Kulangara K, Antoniello K, Markram H (2007) Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci 104:13501–13506. doi:10.1073/pnas.0704391104 PubMedPubMedCentral

Roberts TPL, Khan SY, Rey M et al (2010) MEG detection of delayed auditory evoked responses in autism spectrum disorders: towards an imaging biomarker for autism. Autism Res 3:8–18. doi:10.1002/aur.111 PubMedPubMedCentral

Rogers SJ, Wehner DE, Hagerman R (2001) The behavioral phenotype in fragile X: symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmental disorders. J Dev Behav Pediatr 22:409–417PubMed

Rojas D, Maharajh K, Teale P, Rogers S (2008) Reduced neural synchronization of gamma-band MEG oscillations in first-degree relatives of children with autism. BMC Psychiatry 8:66. doi:10.1186/1471-244X-8-66 PubMedPubMedCentral

Rojas, DC, Singel, D, Steinmetz, S et al. (2014) Decreased left perisylvian GABA concentration in children with autism and unaffected siblings. Neuroimage 86:28–34

Rolf LH, Haarmann FY, Grotemeyer KH, Kehrer H (1993) Serotonin and amino acid content in platelets of autistic children. Acta Psychiatr Scand 87:312–316PubMed

Russo E, Gitto R, Citraro R et al (2012) New AMPA antagonists in epilepsy. Expert Opin Investig Drugs 21:1371–1389. doi:10.1517/13543784.2012.705277 PubMed

Rutter M, Silberg J, O’Connor T, Simonoff E (1999) Genetics and child psychiatry: II empirical research findings. J Child Psychol Psychiatry 40:19–55PubMed

Sanacora G, Zarate CA, Krystal JH, Manji HK (2008) Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 7:426–437. doi:10.1038/nrd2462 PubMedPubMedCentral

Santoro MR, Bray SM, Warren ST (2012) Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu Rev Pathol Mech Dis 7:219–245. doi:10.1146/annurev-pathol-011811-132457

Sato A, Kasai S, Kobayashi T et al (2012) Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex. Nat Commun 3:1292. doi:10.1038/ncomms2295 PubMedPubMedCentral

Schneider T, Przewłocki R (2004) Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 30:80–89. doi:10.1038/sj.npp.1300518

Sebat J, Lakshmi B, Malhotra D et al (2007) Strong association of de novo copy number mutations with autism. Science 316:445–449. doi:10.1126/science.1138659 PubMedPubMedCentral

Serajee FJ, Zhong H, Nabi R, Huq AM (2003) The metabotropic glutamate receptor 8 gene at 7q31: partial duplication and possible association with autism. J Med Genet 40:e42. doi:10.1136/jmg.40.4.e42 PubMedPubMedCentral

Sheng M (2001) The postsynaptic NMDA-receptor—PSD-95 signaling complex in excitatory synapses of the brain. J Cell Sci 114:1251PubMed

Shi L, Linville MC, Tucker EW et al (2005) Differential effects of aging and insulin-like growth factor-1 on synapses in CA1 of rat hippocampus. Cereb Cortex 15:571–577. doi:10.1093/cercor/bhh158 PubMed

Shimmura C, Suda S, Tsuchiya KJ et al (2011) Alteration of plasma glutamate and glutamine levels in children with high-functioning autism. PLoS One 6:e25340. doi:10.1371/journal.pone.0025340 PubMedPubMedCentral

Shimmura C, Suzuki K, Iwata Y et al (2013) Enzymes in the glutamate-glutamine cycle in the anterior cingulate cortex in postmortem brain of subjects with autism. Mol Autism 4:1. doi:10.1186/2040-2392-4-6

Shinohe A, Hashimoto K, Nakamura K et al (2006) Increased serum levels of glutamate in adult patients with autism. Prog Neuropsychopharmacol Biol Psychiatry 30:1472–1477. doi:10.1016/j.pnpbp.2006.06.013 PubMed

Shuang M, Liu J, Jia MX et al (2004) Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios. Am J Med Genet B Neuropsychiatr Genet 131B:48–50. doi:10.1002/ajmg.b.30025 PubMed

Soczynska JK, Mansur RB, Brietzke E et al (2012) Novel therapeutic targets in depression: minocycline as a candidate treatment. Behav Brain Res 235:302–317. doi:10.1016/j.bbr.2012.07.026 PubMed

Soorya L, Kolevzon A, Zweifach J et al (2013) Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Mol Autism 4:18. doi:10.1186/2040-2392-4-18 PubMedPubMedCentral

Szulc A, Galinska B, Tarasow E et al (2011) Proton magnetic resonance spectroscopy study of brain metabolite changes after antipsychotic treatment. Pharmacopsychiatry 44:148–157. doi:10.1055/s-0031-1279739 PubMed

Talebizadeh Z, Lam DY, Theodoro MF et al (2006) Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism. J Med Genet 43:e21. doi:10.1136/jmg.2005.036897 PubMedPubMedCentral

Tarabeux J, Kebir O, Gauthier J et al (2011) Rare mutations in N-methyl-d-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. Transl Psychiatry 1:e55. doi:10.1038/tp.2011.52 PubMedPubMedCentral

Telfeian AE, Federoff HJ, Leone P et al (2000) Overexpression of GluR6 in rat hippocampus produces seizures and spontaneous nonsynaptic bursting in vitro. Neurobiol Dis 7:362–374. doi:10.1006/nbdi.2000.0294 PubMed

Tirouvanziam R, Obukhanych TV, Laval J et al (2011) Distinct plasma profile of polar neutral amino acids, leucine, and glutamate in children with autism spectrum disorders. J Autism Dev Disord 42:827–836. doi:10.1007/s10803-011-1314-x

Tuchman R, Alessandri M, Cuccaro M (2010a) Autism spectrum disorders and epilepsy: moving towards a comprehensive approach to treatment. Brain Dev 32:719–730. doi:10.1016/j.braindev.2010.05.007 PubMed

Tuchman R, Cuccaro M, Alessandri M (2010b) Autism and epilepsy: historical perspective. Brain Dev 32:709–718. doi:10.1016/j.braindev.2010.04.008 PubMed

Vaags AK, Lionel AC, Sato D et al (2012) Rare deletions at the neurexin 3 locus in autism spectrum disorder. Am J Hum Genet 90:133–141. doi:10.1016/j.ajhg.2011.11.025 PubMedPubMedCentral

Vande Wydeven K, Kwan A, Hardan AY, Bernstein JA (2012) Underutilization of genetics services for autism: the importance of parental awareness and provider recommendation. J Genet Counsel 21:803–813. doi:10.1007/s10897-012-9494-x

Wang DD, Englot DJ, Garcia PA et al (2012) Minocycline- and tetracycline-class antibiotics are protective against partial seizures in vivo. Epilepsy Behav 24:314–318. doi:10.1016/j.yebeh.2012.03.035 PubMedPubMedCentral

Wermter A-K, Kamp-Becker I, Strauch K et al (2008) 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. Am J Med Genet B Neuropsychiatr Genet 147B:535–537. doi:10.1002/ajmg.b.30618 PubMed

Weston MC, Chen H, Swann JW (2012) Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission. J Neurosci 32:11441–11452. doi:10.1523/JNEUROSCI.1283-12.2012 PubMedPubMedCentral

White SW, Oswald D, Ollendick T, Scahill L (2009) Anxiety in children and adolescents with autism spectrum disorders. Clin Psychol Rev 29:216–229. doi:10.1016/j.cpr.2009.01.003 PubMedPubMedCentral

Whiteside SP, Port JD, Deacon BJ, Abramowitz JS (2006) A magnetic resonance spectroscopy investigation of obsessive-compulsive disorder and anxiety. Psychiatry Res 146:137–147. doi:10.1016/j.pscychresns.2005.12.006 PubMed

Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP (2005) Suppression of two major fragile X syn×drome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 49:1053–1066. doi:10.1016/j.neuropharm.2005.06.004 PubMed

Yan J, Noltner K, Feng J et al (2008) Neurexin 1alpha structural variants associated with autism. Neurosci Lett 438:368–370. doi:10.1016/j.neulet.2008.04.074 PubMed

Yip J, Soghomonian J–J, Blatt GJ (2007) Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathol 113:559–568. doi:10.1007/s00401-006-0176-3 PubMed

Yonan AL, Alarcón M, Cheng R et al (2003) A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet 73:886–897PubMedPubMedCentral

Yoo HJ, Cho IH, Park M et al (2012) Family based association of GRIN2A and GRIN2B with Korean autism spectrum disorders. Neurosci Lett 512:89–93. doi:10.1016/j.neulet.2012.01.061 PubMed

Zeng L-H, Xu L, Gutmann DH, Wong M (2008) Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol 63:444–453. doi:10.1002/ana.21331 PubMedPubMedCentral

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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