title: The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment.
abstract: 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.
authors.affiliation: Department of Psychology, Campus Delivery 1876, Colorado State University, Fort Collins, CO, 80523, USA, don.rojas@colostate.edu.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Rojas
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D011619:Psychotropic Drugs / Q000627:therapeutic use*; D017470:Receptors, Glutamate / Q000378:metabolism*; D009435:Synaptic Transmission
chemical_list: D018691:Excitatory Amino Acid Antagonists; D011619:Psychotropic Drugs; D017470:Receptors, Glutamate; D018698:Glutamic Acid
references.citation: J Genet Couns. 2012 Dec;21(6):803-13
references.pmid: 22415587
references.citation: Mol Pharmacol. 2009 Jul;76(1):18-24
references.pmid: 19351745
references.citation: J Cell Sci. 2001 Apr;114(Pt 7):1251
references.pmid: 11256991
references.citation: Ann Neurol. 2008 Apr;63(4):444-53
references.pmid: 18389497
references.citation: Nat Rev Drug Discov. 2008 May;7(5):426-37
references.pmid: 18425072
references.citation: Expert Opin Investig Drugs. 2012 Sep;21(9):1371-89
references.pmid: 22788917
references.citation: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7746-50
references.pmid: 12032354
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2010 Jun 5;153B(4):937-47
references.pmid: 20468056
references.citation: J Dev Behav Pediatr. 2013 Apr;34(3):147-55
references.pmid: 23572165
references.citation: Sci Transl Med. 2012 Sep 19;4(152):152ra127
references.pmid: 22993294
references.citation: Autism Res. 2010 Feb;3(1):8-18
references.pmid: 20063319
references.citation: Hippocampus. 2012 Feb;22(2):241-54
references.pmid: 21049485
references.citation: PLoS One. 2011;6(10):e25340
references.pmid: 21998651
references.citation: BMC Neurol. 2010 Oct 11;10:91
references.pmid: 20937127
references.citation: Curr Opin Neurobiol. 2011 Apr;21(2):339-44
references.pmid: 21376567
references.citation: Neuron. 2012 Apr 12;74(1):49-56
references.pmid: 22500629
references.citation: Mol Psychiatry. 2003 Nov;8(11):916-24
references.pmid: 14593429
references.citation: Am J Hum Genet. 2004 Mar;74(3):552-7
references.pmid: 14963808
references.citation: J Can Acad Child Adolesc Psychiatry. 2013 May;22(2):166-71
references.pmid: 23667364
references.citation: Pediatrics. 2011 Sep;128(3):e488-95
references.pmid: 21844053
references.citation: Invest Clin. 1996 Jun;37(2):113-28
references.pmid: 8718922
references.citation: Acta Psychiatr Scand. 1993 May;87(5):312-6
references.pmid: 8517170
references.citation: Nature. 1998 Apr 9;392(6676):601-5
references.pmid: 9580260
references.citation: Invest Clin. 1992;33(1):13-31
references.pmid: 1391074
references.citation: Int J Neuropsychopharmacol. 2013 May;16(4):783-9
references.pmid: 22999292
references.citation: J Cereb Blood Flow Metab. 2011 Nov;31(11):2169-80
references.pmid: 21792244
references.citation: Am J Hum Genet. 2007 Dec;81(6):1289-97
references.pmid: 17999366
references.citation: Eur Arch Psychiatry Clin Neurosci. 2013 Aug;263(5):379-84
references.pmid: 22986449
references.citation: Biol Psychiatry. 2010 Dec 15;68(12):1100-6
references.pmid: 21130222
references.citation: J Neurodev Disord. 2013;5(1):9
references.pmid: 23566357
references.citation: Neurobiol Dis. 2000 Aug;7(4):362-74
references.pmid: 10964607
references.citation: J Med Genet. 2008 Aug;45(8):498-9
references.pmid: 18413371
references.citation: Am J Hum Genet. 2008 Jan;82(1):160-4
references.pmid: 18179894
references.citation: Nat Commun. 2012;3:1292
references.pmid: 23250422
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2008 Apr 1;32(3):911, author reply 912-3
references.pmid: 18160196
references.citation: Psychiatr Genet. 2011 Aug;21(4):212-3
references.pmid: 21085054
references.citation: Neuron. 2007 Dec 20;56(6):955-62
references.pmid: 18093519
references.citation: J Child Neurol. 2007 May;22(5):574-9
references.pmid: 17690064
references.citation: Brain Res Rev. 2009 Oct;61(2):105-23
references.pmid: 19481572
references.citation: Mol Autism. 2013 Apr 27;4(1):9
references.pmid: 23621888
references.citation: Neurosci Biobehav Rev. 2014 Oct;46 Pt 2:228-41
references.pmid: 24548786
references.citation: J Autism Dev Disord. 2001 Dec;31(6):537-43
references.pmid: 11814263
references.citation: J Autism Dev Disord. 1993 Jun;23(2):323-39
references.pmid: 8331050
references.citation: Mol Syndromol. 2012 Apr;2(3-5):186-201
references.pmid: 22670140
references.citation: Neurobiol Dis. 2012 Jul;47(1):135-43
references.pmid: 22504536
references.citation: Annu Rev Pharmacol Toxicol. 2010;50:295-322
references.pmid: 20055706
references.citation: Neurosci Biobehav Rev. 2011 Apr;35(5):1081-8
references.pmid: 21093480
references.citation: Seizure. 2010 Oct;19(8):485-92
references.pmid: 20688545
references.citation: Biol Psychiatry. 2002 Oct 15;52(8):805-10
references.pmid: 12372652
references.citation: Eur J Neurosci. 1995 Oct 1;7(10):2036-41
references.pmid: 8542061
references.citation: Alcohol Clin Exp Res. 2002 Dec;26(12):1779-93
references.pmid: 12500101
references.citation: J Autism Dev Disord. 2010 Nov;40(11):1412-6
references.pmid: 20213249
references.citation: Am J Hum Genet. 2001 Sep;69(3):570-81
references.pmid: 11481586
references.citation: J Med Genet. 2006 May;43(5):e21
references.pmid: 16648374
references.citation: J Physiol. 2005 Jan 1;562(Pt 1):65-72
references.pmid: 15513934
references.citation: Pharmacol Biochem Behav. 2012 Feb;100(4):850-4
references.pmid: 21315104
references.citation: Am J Psychiatry. 2010 Nov;167(11):1349-56
references.pmid: 20889652
references.citation: Pharmacology. 2012;89(3-4):156-62
references.pmid: 22414722
references.citation: Transl Psychiatry. 2013 Jul 09;3:e279
references.pmid: 23838890
references.citation: J Child Adolesc Psychopharmacol. 2006 Oct;16(5):517-24
references.pmid: 17069541
references.citation: Am J Hum Genet. 2003 Oct;73(4):886-97
references.pmid: 13680528
references.citation: Am J Intellect Dev Disabil. 2010 Nov;115(6):461-72
references.pmid: 20945999
references.citation: Transl Psychiatry. 2011 Nov 15;1:e55
references.pmid: 22833210
references.citation: Mol Psychiatry. 2002;7(3):302-10
references.pmid: 11920157
references.citation: J Autism Dev Disord. 2014 Apr;44(4):958-64
references.pmid: 24272415
references.citation: Dev Med Child Neurol. 2005 Aug;47(8):551-5
references.pmid: 16108456
references.citation: J Neurosci. 2013 Oct 2;33(40):15767-78
references.pmid: 24089484
references.citation: Psychopharmacology (Berl). 2013 Jul;228(1):75-84
references.pmid: 23436129
references.citation: J Neural Transm (Vienna). 1998;105(4-5):525-35
references.pmid: 9720980
references.citation: Am J Ment Retard. 2008 Nov;113(6):427-38
references.pmid: 19127654
references.citation: Arch Gen Psychiatry. 2007 Feb;64(2):193-200
references.pmid: 17283286
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2005 Jan 5;132B(1):74-5
references.pmid: 15389766
references.citation: Trends Neurosci. 2004 Jul;27(7):370-7
references.pmid: 15219735
references.citation: Drug Discov Today. 2013 Feb;18(3-4):173-84
references.pmid: 23092894
references.citation: Brain Res. 2011 Mar 22;1380:198-205
references.pmid: 21185269
references.citation: Res Autism Spectr Disord. 2012 Oct 1;6(4):1311-1320
references.pmid: 23162607
references.citation: Neurobiol Aging. 2005 May;26(5):665-72
references.pmid: 15708441
references.citation: Neurosci Lett. 2008 Jun 27;438(3):368-70
references.pmid: 18490107
references.citation: Psychiatr Genet. 2013 Dec;23(6):262-6
references.pmid: 24064682
references.citation: BMC Psychiatry. 2008 Aug 01;8:66
references.pmid: 18673566
references.citation: Cereb Cortex. 2015 Jan;25(1):271-9
references.pmid: 23968838
references.citation: Epilepsy Behav. 2011 Dec;22(4):617-40
references.pmid: 22056342
references.citation: Neurobiol Dis. 2006 Jan;21(1):217-27
references.pmid: 16087343
references.citation: Brain Dev. 2010 Oct;32(9):719-30
references.pmid: 20558021
references.citation: Res Autism Spectr Disord. 2014 Jan;8(1):44-51
references.pmid: 24459534
references.citation: Am J Hum Genet. 2012 Jan 13;90(1):133-41
references.pmid: 22209245
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2004 Nov 15;131B(1):48-50
references.pmid: 15389769
references.citation: J Med Genet. 2003 Apr;40(4):e42
references.pmid: 12676915
references.citation: J Autism Dev Disord. 2009 Dec;39(12):1629-35
references.pmid: 19609663
references.citation: Sci Transl Med. 2011 Jan 5;3(64):64ra1
references.pmid: 21209411
references.citation: Neurology. 2001 Nov 13;57(9):1618-28
references.pmid: 11706102
references.citation: J Magn Reson Imaging. 2011 May;33(5):1262-7
references.pmid: 21509888
references.citation: J Med Genet. 2009 Apr;46(4):266-71
references.pmid: 19126569
references.citation: J Am Acad Child Adolesc Psychiatry. 2001 Jun;40(6):658-65
references.pmid: 11392343
references.citation: Trends Mol Med. 2011 Feb;17(2):78-87
references.pmid: 21115397
references.citation: Am J Psychiatry. 2004 Apr;161(4):662-9
references.pmid: 15056512
references.citation: Mol Autism. 2013 Mar 26;4(1):6
references.pmid: 23531457
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2008 Jun 5;147B(4):535-7
references.pmid: 18189281
references.citation: BMC Med Genet. 2004 Apr 16;5:10
references.pmid: 15090072
references.citation: Transl Psychiatry. 2012 Jul 17;2:e142
references.pmid: 22806213
references.citation: Biol Psychiatry. 2007 Feb 15;61(4):465-73
references.pmid: 17276747
references.citation: Behav Brain Res. 2012 Dec 1;235(2):302-17
references.pmid: 22963995
references.citation: J Clin Psychopharmacol. 2007 Jun;27(3):317-8
references.pmid: 17502791
references.citation: Eur J Neurosci. 2007 Nov;26(9):2481-95
references.pmid: 17986028
references.citation: Mol Autism. 2013 May 24;4(1):15
references.pmid: 23706040
references.citation: J Autism Dev Disord. 2012 May;42(5):827-36
references.pmid: 21713591
references.citation: J Dev Behav Pediatr. 2001 Dec;22(6):409-17
references.pmid: 11773805
references.citation: J Autism Dev Disord. 2011 Apr;41(4):447-54
references.pmid: 20652388
references.citation: Psychopharmacology (Berl). 2007 Mar;191(1):141-7
references.pmid: 17016714
references.citation: J Child Adolesc Psychopharmacol. 2011 Dec;21(6):565-9
references.pmid: 22136091
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13501-6
references.pmid: 17675408
references.citation: Cell. 2011 Jul 22;146(2):247-61
references.pmid: 21784246
references.citation: Epilepsy Behav. 2012 Jul;24(3):314-8
references.pmid: 22579030
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2006 Dec 30;30(8):1472-7
references.pmid: 16863675
references.citation: Anat Rec (Hoboken). 2011 Oct;294(10):1635-45
references.pmid: 21901840
references.citation: Pharmacopsychiatry. 2011 Jun;44(4):148-57
references.pmid: 21710405
references.citation: Neurosci Lett. 2012 Mar 23;512(2):89-93
references.pmid: 22326929
references.citation: Hum Mol Genet. 2001 Apr 15;10(9):973-82
references.pmid: 11392322
references.citation: Annu Rev Pathol. 2012;7:219-45
references.pmid: 22017584
references.citation: Nat Genet. 2003 May;34(1):27-9
references.pmid: 12669065
references.citation: Genet Med. 2007 May;9(5):268-74
references.pmid: 17505203
references.citation: J Child Neurol. 1999 Aug;14(8):524-8
references.pmid: 10456763
references.citation: Neuroreport. 2005 Feb 8;16(2):183-6
references.pmid: 15671874
references.citation: Brain Res. 2011 Mar 22;1380:42-77
references.pmid: 21129364
references.citation: JAMA Psychiatry. 2013 Sep;70(9):964-74
references.pmid: 23903694
references.citation: Am J Hum Genet. 2009 Oct;85(4):503-14
references.pmid: 19804849
references.citation: Neuropsychopharmacology. 2005 Jan;30(1):80-9
references.pmid: 15238991
references.citation: Genet Couns. 2012;23(4):505-11
references.pmid: 23431752
references.citation: Neuropharmacology. 2005 Dec;49(7):1053-66
references.pmid: 16054174
references.citation: Genet Med. 2011 Apr;13(4):278-94
references.pmid: 21358411
references.citation: Cereb Cortex. 2005 May;15(5):571-7
references.pmid: 15319312
references.citation: PLoS One. 2013;8(2):e56639
references.pmid: 23468870
references.citation: J Neurodev Disord. 2013 Aug 28;5(1):20
references.pmid: 23981510
references.citation: Nat Genet. 2007 Mar;39(3):319-28
references.pmid: 17322880
references.citation: Pediatrics. 2009 Nov;124(5):1395-403
references.pmid: 19805460
references.citation: Brain Dev. 2010 Oct;32(9):709-18
references.pmid: 20510557
references.citation: Curr Opin Neurobiol. 2007 Feb;17(1):103-11
references.pmid: 17275283
references.citation: Dis Markers. 2013;35(5):281-6
references.pmid: 24167375
references.citation: Neuroimage. 2014 Feb 1;86:1-9
references.pmid: 23707581
references.citation: J Neurosci. 2010 Feb 10;30(6):2115-29
references.pmid: 20147539
references.citation: Autism Res. 2008 Jun;1(3):193-7
references.pmid: 19360666
references.citation: PLoS One. 2012;7(7):e38786
references.pmid: 22848344
references.citation: J Neurodev Disord. 2009 Jun;1(2):172-81
references.pmid: 20664807
references.citation: Acta Neuropathol. 2007 May;113(5):559-68
references.pmid: 17235515
references.citation: Science. 2007 Apr 20;316(5823):445-9
references.pmid: 17363630
references.citation: J Child Psychol Psychiatry. 1999 Jan;40(1):19-55
references.pmid: 10102725
references.citation: Psychol Med. 1995 Jan;25(1):63-77
references.pmid: 7792363
references.citation: J Neurosci. 2012 Aug 15;32(33):11441-52
references.pmid: 22895726
references.citation: Clin Psychol Rev. 2009 Apr;29(3):216-29
references.pmid: 19223098
references.citation: Mol Autism. 2013 Jun 11;4(1):18
references.pmid: 23758760
references.citation: J Autism Dev Disord. 2003 Feb;33(1):93-7
references.pmid: 12708584
references.citation: Autism Res. 2013 Feb;6(1):1-10
references.pmid: 23166003
references.citation: Am J Psychiatry. 2006 Dec;163(12):2189-92
references.pmid: 17151175
references.citation: Psychiatry Res. 2006 Mar 31;146(2):137-47
references.pmid: 16507346