# Autism Spectrum Disorder: Focus on Glutamatergic Neurotransmission **Authors:** Martina Montanari, Giuseppina Martella, Paola Bonsi, Maria Meringolo PMC · DOI: 10.3390/ijms23073861 · International Journal of Molecular Sciences · 2022-03-31 ## TL;DR This review explores how disruptions in glutamate signaling may contribute to autism and highlights potential treatments targeting this system. ## Contribution The paper synthesizes current evidence on glutamatergic dysfunction in autism and its therapeutic implications. ## Key findings - Glutamatergic gene expression and metabolic pathways are altered in individuals with autism. - Animal models show deficits in glutamate neurotransmission and synaptic proteins. - Clinical trials are testing existing glutamatergic drugs for autism treatment. ## Abstract Disturbances in the glutamatergic system have been increasingly documented in several neuropsychiatric disorders, including autism spectrum disorder (ASD). Glutamate-centered theories of ASD are based on evidence from patient samples and postmortem studies, as well as from studies documenting abnormalities in glutamatergic gene expression and metabolic pathways, including changes in the gut microbiota glutamate metabolism in patients with ASD. In addition, preclinical studies on animal models have demonstrated glutamatergic neurotransmission deficits and altered expression of glutamate synaptic proteins. At present, there are no approved glutamatergic drugs for ASD, but several ongoing clinical trials are currently focusing on evaluating in autistic patients glutamatergic pharmaceuticals already approved for other conditions. In this review, we provide an overview of the literature concerning the role of glutamatergic neurotransmission in the pathophysiology of ASD and as a potential target for novel treatments. ## Linked entities - **Chemicals:** glutamate (PubChem CID 611) - **Diseases:** autism spectrum disorder (MONDO:0005258), ASD (MONDO:0006664) ## Full-text entities - **Genes:** Dnmt3b (DNA methyltransferase 3B) [NCBI Gene 13436] {aka MmuIIIB}, Dlg4 (discs large MAGUK scaffold protein 4) [NCBI Gene 13385] {aka Dlgh4, PSD-95, PSD95, SAP90, SAP90A}, Cntnap2 (contactin associated protein-like 2) [NCBI Gene 66797] {aka 5430425M22Rik, Caspr2, mKIAA0868}, GRM8 (glutamate metabotropic receptor 8) [NCBI Gene 2918] {aka GLUR8, GPRC1H, MGLUR8, mGlu8}, GRID1 (glutamate ionotropic receptor delta type subunit 1) [NCBI Gene 2894] {aka GluD1, GluD1-b}, GRIA2 (glutamate ionotropic receptor AMPA type subunit 2) [NCBI Gene 2891] {aka GLUR2, GLURB, GluA2, GluR-K2, HBGR2, NEDLIB}, GRM5 (glutamate metabotropic receptor 5) [NCBI Gene 2915] {aka GPRC1E, MGLUR5, PPP1R86, mGlu5}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, GRIN2B (glutamate ionotropic receptor NMDA type subunit 2B) [NCBI Gene 2904] {aka DEE27, EIEE27, GluN2B, MRD6, NMDAR2B, NR2B}, Tsc1 (TSC complex subunit 1) [NCBI Gene 64930], Grm5 (glutamate receptor, metabotropic 5) [NCBI Gene 108071] {aka 6430542K11Rik, Glu5R, Gprc1e, mGluR5, mGluR5b}, Gabrg3 (gamma-aminobutyric acid type A receptor, subunit gamma 3) [NCBI Gene 14407] {aka 6330406O05Rik, B230362M20Rik, Gabrg-3}, Grik2 (glutamate receptor, ionotropic, kainate 2 (beta 2)) [NCBI Gene 14806] {aka C130030K03Rik, GluK2, Glur-6, Glur6, Glurbeta2}, Shank3 (SH3 and multiple ankyrin repeat domains 3) [NCBI Gene 58234] {aka Spank-2, proSAP2}, Slc1a1 (solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1) [NCBI Gene 20510] {aka D130048G10Rik, EAAC1, EAAC2, EAAT3, MEAAC1}, Dlg3 (discs large MAGUK scaffold protein 3) [NCBI Gene 53310] {aka Dlgh3, SAP102, mKIAA1232}, Dnmt3a (DNA methyltransferase 3 alpha) [NCBI Gene 444984], Nlgn3 (neuroligin 3) [NCBI Gene 171297], Dnmt1 (DNA methyltransferase 1) [NCBI Gene 84350], Grm3 (glutamate receptor, metabotropic 3) [NCBI Gene 108069] {aka 0710001G23Rik, Gprc1c, mGlu3, mGluR3}, Nlgn1 (neuroligin 1) [NCBI Gene 116647], Grin2a (glutamate ionotropic receptor NMDA type subunit 2A) [NCBI Gene 24409] {aka GluN2A, NMDAR2A, NR2A}, Gabra5 (gamma-aminobutyric acid type A receptor subunit alpha 5) [NCBI Gene 29707], Grik4 (glutamate receptor, ionotropic, kainate 4) [NCBI Gene 110637] {aka 6330551K01Rik, GluK4, GluRgamma1, KA-1, KA1}, GRIN2A (glutamate ionotropic receptor NMDA type subunit 2A) [NCBI Gene 2903] {aka EPND, FESD, GluN2A, LKS, NMDAR2A, NR2A}, Gria1 (glutamate receptor, ionotropic, AMPA1 (alpha 1)) [NCBI Gene 14799] {aka 2900051M01Rik, Glr-1, Glr1, GluA1, GluR-A, GluRA}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, Gria4 (glutamate receptor, ionotropic, AMPA4 (alpha 4)) [NCBI Gene 14802] {aka GluA4, GluR-D, Glur-4, Glur4, Gluralpha4, spkw1}, Mecp2 (methyl CpG binding protein 2) [NCBI Gene 17257] {aka 1500041B07Rik, D630021H01Rik, Mbd5, WBP10}, GRIA1 (glutamate ionotropic receptor AMPA type subunit 1) [NCBI Gene 2890] {aka GLUH1, GLUR1, GLURA, GluA1, HBGR1, MRD67}, Grin1 (glutamate receptor, ionotropic, NMDA1 (zeta 1)) [NCBI Gene 14810] {aka GluN1, GluRdelta1, GluRzeta1, M100174, NMD-R1, NMDAR1}, Gria3 (glutamate receptor, ionotropic, AMPA3 (alpha 3)) [NCBI Gene 53623] {aka 2900064I19Rik, GluA3, GluR-C, GluR-K3, Glur-3, Glur3}, Nlgn3 (neuroligin 3) [NCBI Gene 245537] {aka A230085M13Rik, HNL3, NL3, NLG3}, Slc1a3 (solute carrier family 1 (glial high affinity glutamate transporter), member 3) [NCBI Gene 20512] {aka B430115D02Rik, Eaat1, GLAST, GLAST-1, GLU-T, GluT-1}, Mecp2 (methyl CpG binding protein 2) [NCBI Gene 29386] {aka MECP2_e1}, Gad1 (glutamate decarboxylase 1) [NCBI Gene 14415] {aka EP10, Gad-1}, Gabrb3 (GABRB3, gamma-aminobutyric acid type A receptor subunit beta 3) [NCBI Gene 14402] {aka A230092K12Rik, Cp1, Gabrb-3, beta3}, GAD1 (glutamate decarboxylase 1) [NCBI Gene 2571] {aka CPSQ1, DEE89, GAD, GAD-67, SCP}, Tsc2 (TSC complex subunit 2) [NCBI Gene 22084] {aka Nafld, Tcs2}, Gria2 (glutamate ionotropic receptor AMPA type subunit 2) [NCBI Gene 29627] {aka GluA2, GluR-K2, GluR2, gluR-B}, GRIP1 (glutamate receptor interacting protein 1) [NCBI Gene 23426] {aka FRASRS3, GRIP}, Pten (phosphatase and tensin homolog) [NCBI Gene 19211] {aka 2310035O07Rik, A130070J02Rik, B430203M17Rik, MMAC1, PTENbeta, TEP1}, Tsc2 (TSC complex subunit 2) [NCBI Gene 24855] {aka Rc}, Fmr1 (fragile X messenger ribonucleoprotein 1) [NCBI Gene 24948] {aka FMRP}, GRM7 (glutamate metabotropic receptor 7) [NCBI Gene 2917] {aka GLUR7, GPRC1G, MGLU7, MGLUR7, NEDSHBA, PPP1R87}, Grin1 (glutamate ionotropic receptor NMDA type subunit 1) [NCBI Gene 24408] {aka GluN1, NMDAR1, NR1}, Grin2b (glutamate receptor, ionotropic, NMDA2B (epsilon 2)) [NCBI Gene 14812] {aka GluN2B, GluRepsilon2, NR2B, Nmdar2b}, Shank2 (SH3 and multiple ankyrin repeat domains 2) [NCBI Gene 171093] {aka CortBP1, ProSAP1, Shank2E, Spank-3}, Slc1a2 (solute carrier family 1 (glial high affinity glutamate transporter), member 2) [NCBI Gene 20511] {aka 1700091C19Rik, 2900019G14Rik, Eaat2, GLT-1, GLT1, MGLT1}, Grin2a (glutamate receptor, ionotropic, NMDA2A (epsilon 1)) [NCBI Gene 14811] {aka GluN2A, GluRepsilon1, NMDAR2A, NR2A}, Shank3 (SH3 and multiple ankyrin repeat domains 3) [NCBI Gene 59312] {aka Prosap2, Spank-2}, GRIK4 (glutamate ionotropic receptor kainate type subunit 4) [NCBI Gene 2900] {aka EAA1, GRIK, GluK4, GluK4-2, KA1}, GAD2 (glutamate decarboxylase 2) [NCBI Gene 2572] {aka GAD65}, Gad2 (glutamic acid decarboxylase 2) [NCBI Gene 14417] {aka 6330404F12Rik, GAD(65), GAD65, Gad-2}, Eif4ebp2 (eukaryotic translation initiation factor 4E binding protein 2) [NCBI Gene 13688] {aka 2810011I19Rik, 4E-BP2, PHAS-II}, Gria1 (glutamate ionotropic receptor AMPA type subunit 1) [NCBI Gene 50592] {aka GluA1, gluR-A}, Gria2 (glutamate receptor, ionotropic, AMPA2 (alpha 2)) [NCBI Gene 14800] {aka GluA2, GluR-B, Glur-2, Glur2, gluR-K2}, GRIK5 (glutamate ionotropic receptor kainate type subunit 5) [NCBI Gene 2901] {aka EAA2, GRIK2, GluK5, KA2}, Nlgn1 (neuroligin 1) [NCBI Gene 192167] {aka 6330415N05Rik, NL1, Nlg1, mKIAA1070}, Dnmt1 (DNA methyltransferase 1) [NCBI Gene 13433] {aka Cxxc9, Dnmt, Dnmt1o, MCMT, MTase, Met-1} - **Diseases:** depression (MESH:D003866), Alzheimer's and Parkinson's diseases (MESH:D010300), GABAergic dysfunction (MESH:D006331), repetitive (MESH:D012090), ASD;Rare (MESH:D035583), anxiety (MESH:D001007), focal epilepsy (MESH:D004828), ADHD (MESH:D001289), Glu (MESH:C537425), neurotoxic (MESH:D020258), neurologic disease (MESH:D020271), deficits (MESH:D009461), hyperactivity (MESH:D006948), developmental defects (MESH:D000094602), calcium (MESH:D002128), cognitive and behavioral deficits (MESH:D003072), viral infections (MESH:D014777), GI problems (MESH:D019973), neurodevelopmental abnormalities (MESH:D063647), ASD (MESH:D000067877), neuroinflammation (MESH:D000090862), bipolar disorder (MESH:D001714), repetitive and stereotyped behaviors (MESH:D019956), immune dysfunctions (MESH:D007154), constipation (MESH:D003248), communication difficulties (MESH:D003147), abnormal social behaviors (MESH:D001523), behavioral deficits (MESH:D019958), abdominal pain (MESH:D015746), like (MESH:C537419), mood disorders (MESH:D019964), aggressive behavior (MESH:D010554), schizophrenia (MESH:D012559), FXS (MESH:D005600), neurological and neuropsychiatric disorders (MESH:D009422), inflammatory (MESH:D007249), neurodevelopmental disorder (MESH:D002658), Autism (MESH:D001321), movements (MESH:D009069), seizure (MESH:D012640), epilepsy (MESH:D004827), infections (MESH:D007239), neurodevelopmental disease (MESH:D004194), Rett (MESH:D015518), gastric reflux (MESH:D005764), ASD disorders (MESH:D002659), intellectual disability (MESH:D008607), diarrhea (MESH:D003967) - **Chemicals:** d-cycloserine (MESH:D003523), cortisol (MESH:D006854), Poly(I:C) (MESH:D011070), 2-keto-glutaramic acid (-), steroids (MESH:D013256), carbohydrates (MESH:D002241), Risperidone (MESH:D018967), Creatine (MESH:D003401), Riluzole (MESH:D019782), Glutamine (MESH:D005973), aspartate (MESH:D001224), Glu (MESH:D018698), 2-methyl-6-(phenylethynyl) pyridine (MESH:C121465), MK-801 (MESH:D016291), progesterone (MESH:D011374), NMDA (MESH:D016202), Memantine (MESH:D008559), fenobam (MESH:C032794), endocannabinoid (MESH:D063388), Aripiprazole (MESH:D000068180), VPA (MESH:D014635), amino acids (MESH:D000596), lamotrigine (MESH:D000077213), RO4917523 (MESH:C000596770), JNJ16259685 (MESH:C495417), GABA (MESH:D005680), AMPA (MESH:D018350), AFQ056 (MESH:C581397) - **Species:** Clostridium botulinum (species) [taxon 1491], Eggerthella lenta (species) [taxon 84112], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116], Phocaeicola vulgatus (species) [taxon 821], Mus musculus (house mouse, species) [taxon 10090] - **Mutations:** R451C, R704C, p.Ala636Thr, Glu/glutamine, R215H, cysteine/Glu ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC8998955/full.md ## Figures 2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC8998955/full.md ## References 354 references — full list in the complete paper: https://tomesphere.com/paper/PMC8998955/full.md --- Source: https://tomesphere.com/paper/PMC8998955