Neuroinflammation and glutamatergic signaling (WP5083)
Homo sapiens
This pathway shows the relation between neuroinflammation and glutamatergic signaling. Pre-synaptic neurons release glutamate, which acts on various receptors (kainate, metabotropic, AMPA and NMDA), thereby regulating LTP, LDP, neuronal survival and proliferation. Glutamate retro-signaling negatively regulates its exocytotic release. The remainder of glutamate is taken up by astrocytes through EAAT1-4. Glutamine is generated from blood-derived glucose, transported to pre-synaptic neurons and converted into glutamate. Alternatively, glucose is converted into D-serine, which functions as co-agonist for NMDARs and is broken down by DAAO. CNS inflammation induces M1 and M2 microglia, which modulate neuronal and astrocyte function.
For a description of pathway objects, see the WikiPathways Legend.
Authors
Lisa Koole , Friederike Ehrhart , Lauren J. Dupuis , Eric Weitz , Finterly Hu , Egon Willighagen , and Daniela DiglesActivity
Discuss this pathway
Check for ongoing discussions or start your own.
Cited In
- Interactive neuroinflammation pathways and transcriptomics-based identification of drugs and chemical compounds for schizophrenia (2023).
- Characterization and comparative profiling of piRNAs in serum biopsies of pediatric Wilms tumor patients (2025).
- Integration of proteomics and bioinformatics in traumatic brain injury biomarker discovery.
- Enhanced therapeutic effects of hypoxia-preconditioned mesenchymal stromal cell-derived extracellular vesicles in renal ischemic injury (2025).
Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.
Organisms
Homo sapiensCommunities
ONTOX Serious Request 2024 - MetaKidsAnnotations
Cell Type Ontology
astrocyte glial cell neuron microglial cellPathway Ontology
signaling pathway pertinent to immunity neuropsychiatric disease pathway signaling pathway pertinent to the brain and nervous systemLabel | Type | Compact URI | Comment |
---|---|---|---|
superoxide | Metabolite | chebi:18421 | |
NH3(+) | Metabolite | chebi:29421 | |
LPS | Metabolite | chebi:16412 | |
H2O2 | Metabolite | chebi:16240 | |
nitric oxide | Metabolite | chebi:16480 | |
Acetyl-CoA | Metabolite | chebi:15351 | |
glutamate | Metabolite | chebi:14321 | |
L-Aspartate | Metabolite | chebi:17053 | |
PHP | Metabolite | chebi:18110 | |
PP3 | Metabolite | wikidata:Q27088431 | |
glutamine | Metabolite | chebi:28300 | |
2-oxoglutarate | Metabolite | chebi:16810 | |
Mg²⁺ | Metabolite | chebi:18420 | |
L-serine | Metabolite | chebi:17115 | |
H⁺ | Metabolite | chebi:15378 | |
D-serine | Metabolite | chebi:35247 | |
cAMP | Metabolite | chebi:17489 | |
1,3-diglycerides | Metabolite | chebi:47777 | |
Glycine | Metabolite | chebi:15428 | |
3PG | Metabolite | chebi:17138 | |
1,2-diglycerides | Metabolite | chebi:49172 | |
3-Phosphoserine | Metabolite | chebi:37712 | |
pyruvate | Metabolite | chebi:15361 | |
NAD+ | Metabolite | chebi:15846 | |
Ca²⁺ | Metabolite | chebi:29108 | |
2-ketoglutarate | Metabolite | chebi:16810 | |
NADH | Metabolite | chebi:16908 | |
glucose | Metabolite | chebi:17234 | |
IL13RA1 | GeneProduct | ncbigene:3597 | |
NFKB2 | GeneProduct | ncbigene:4791 | |
IL1R2 | GeneProduct | ncbigene:7850 | |
LIF | GeneProduct | ncbigene:3976 | |
TRAF5 | GeneProduct | ncbigene:7188 | |
IL4 | GeneProduct | ncbigene:3565 | |
TNFRSF1B | GeneProduct | ncbigene:7133 | |
IL4R | GeneProduct | ncbigene:3566 | |
GFAP | GeneProduct | ncbigene:2670 | |
IL6 | GeneProduct | ncbigene:3569 | |
SMAD2 | GeneProduct | ncbigene:4087 | |
NGF | GeneProduct | ncbigene:4803 | |
IL1A | GeneProduct | ncbigene:3552 | |
IL6ST | GeneProduct | ncbigene:3572 | |
IFNG | GeneProduct | ncbigene:3458 | |
TGFBR2 | GeneProduct | ncbigene:7048 | |
STAT3 | GeneProduct | ncbigene:6774 | |
TNFRSF1A | GeneProduct | ncbigene:7132 | |
BDNF | GeneProduct | ncbigene:627 | |
TGFB1 | GeneProduct | ncbigene:7040 | |
LTA | GeneProduct | ncbigene:4049 | |
IL13 | GeneProduct | ncbigene:3596 | |
IL10RB | GeneProduct | ncbigene:3588 | |
JAK1 | GeneProduct | ncbigene:3716 | |
STAT1 | GeneProduct | ncbigene:6772 | |
TGFBR3 | GeneProduct | ncbigene:7049 | |
DAO | GeneProduct | ncbigene:1610 | |
IL12A | GeneProduct | ncbigene:3592 | |
SOCS3 | GeneProduct | ncbigene:9021 | |
STAT6 | GeneProduct | ncbigene:6778 | |
IL10RA | GeneProduct | ncbigene:3587 | |
IRS1 | GeneProduct | ncbigene:3667 | |
AKT1 | GeneProduct | ncbigene:207 | |
TGFB2 | GeneProduct | ncbigene:7042 | |
IL6R | GeneProduct | ncbigene:3570 | |
SMAD3 | GeneProduct | ncbigene:4088 | |
IL1R1 | GeneProduct | ncbigene:3554 | |
TGFBR1 | GeneProduct | ncbigene:7046 | |
SMAD7 | GeneProduct | ncbigene:4092 | |
INSR | GeneProduct | ncbigene:3643 | |
IL12B | GeneProduct | ncbigene:3593 | |
FGF2 | GeneProduct | ncbigene:2247 | |
NOS1 | GeneProduct | ncbigene:4842 | |
TGFB3 | GeneProduct | ncbigene:7043 | |
IL1B | GeneProduct | ncbigene:3553 | |
SMAD4 | GeneProduct | ncbigene:4089 | |
NFKB1 | GeneProduct | ncbigene:4790 | |
GRIN1 | GeneProduct | ncbigene:2902 | |
GRM8 | GeneProduct | ncbigene:2918 | |
GRIK4 | GeneProduct | ncbigene:2900 | |
GRIN2A | GeneProduct | ncbigene:2903 | |
GRIK3 | GeneProduct | ncbigene:2899 | |
PPP1CC | GeneProduct | ncbigene:5501 | |
GRIN2D | GeneProduct | ncbigene:2906 | |
GRIK5 | GeneProduct | ncbigene:2901 | |
GRM7 | GeneProduct | ncbigene:2917 | |
CAMKK2 | GeneProduct | ncbigene:10645 | |
MAPK1 | GeneProduct | ncbigene:5594 | |
SHMT1 | GeneProduct | ncbigene:6470 | |
CAMK4 | GeneProduct | ncbigene:814 | |
PHGDH | GeneProduct | ncbigene:26227 | |
GOT1 | GeneProduct | ncbigene:2805 | |
CAMK2A | GeneProduct | ncbigene:815 | |
LRRC8B | GeneProduct | ncbigene:23507 | |
LRRC8E | GeneProduct | ncbigene:80131 | |
LRRC8A | GeneProduct | ncbigene:56262 | |
SRR | GeneProduct | ncbigene:63826 | |
GRIN2C | GeneProduct | ncbigene:2905 | |
SLC1A4 | GeneProduct | ncbigene:6509 | |
GRIA3 | GeneProduct | ncbigene:2892 | |
PSPH | GeneProduct | ncbigene:5723 | |
GRIA4 | GeneProduct | ncbigene:2893 | |
GRIK2 | GeneProduct | ncbigene:2898 | |
GRIA2 | GeneProduct | ncbigene:2891 | |
GRM4 | GeneProduct | ncbigene:2914 | |
GRIN3B | GeneProduct | ncbigene:116444 | |
PLCB2 | GeneProduct | ncbigene:5330 | |
PRKACA | GeneProduct | ncbigene:5566 | |
PRKCG | GeneProduct | ncbigene:5582 | |
ADCY1 | GeneProduct | ncbigene:107 | |
LRRC8D | GeneProduct | ncbigene:55144 | |
PSAT1 | GeneProduct | ncbigene:29968 | |
PRKCB | GeneProduct | ncbigene:5579 | |
PLCB1 | GeneProduct | ncbigene:23236 | |
PPP1CB | GeneProduct | ncbigene:5500 | |
SLC38A1 | GeneProduct | ncbigene:81539 | |
SLC6A9 | GeneProduct | ncbigene:6536 | |
CAMK2G | GeneProduct | ncbigene:818 | |
PDHA1 | GeneProduct | ncbigene:5160 | |
GRM1 | GeneProduct | ncbigene:2911 | |
ADCY3 | GeneProduct | ncbigene:109 | |
PRKCA | GeneProduct | ncbigene:5578 | |
MAPK3 | GeneProduct | ncbigene:5595 | |
CAMKK1 | GeneProduct | ncbigene:84254 | |
PLCB3 | GeneProduct | ncbigene:5331 | |
PPP1CA | GeneProduct | ncbigene:5499 | |
NSMF | GeneProduct | ncbigene:26012 | Synonym: Jacob |
GRIN2B | GeneProduct | ncbigene:2904 | |
SLC1A6 | GeneProduct | ncbigene:6511 | |
SHMT2 | GeneProduct | ncbigene:6472 | |
DLAT | GeneProduct | ncbigene:1737 | |
DLD | GeneProduct | ncbigene:1738 | |
ADCY8 | GeneProduct | ncbigene:114 | |
DISC1 | GeneProduct | ncbigene:27185 | |
LRRC8C | GeneProduct | ncbigene:84230 | |
SLC38A2 | GeneProduct | ncbigene:54407 | |
CFL1 | GeneProduct | ncbigene:1072 | |
TRPM4 | GeneProduct | ncbigene:54795 | |
PLCB4 | GeneProduct | ncbigene:5332 | |
CAMK2B | GeneProduct | ncbigene:816 | |
GRM2 | GeneProduct | ncbigene:2912 | |
GRIK1 | GeneProduct | ncbigene:2897 | |
CAMK2D | GeneProduct | ncbigene:817 | |
GRIA1 | GeneProduct | ncbigene:2890 | |
SLC1A1 | GeneProduct | ncbigene:6505 | |
CALM1 | GeneProduct | ncbigene:801 | |
GRIN3A | GeneProduct | ncbigene:116443 | |
GLS | GeneProduct | ncbigene:2744 | |
GLS2 | GeneProduct | ncbigene:27165 | |
SLC17A6 | GeneProduct | ncbigene:57084 | |
SLC17A7 | GeneProduct | ncbigene:57030 | |
SLC38A5 | GeneProduct | ncbigene:92745 | |
SLC38A3 | GeneProduct | ncbigene:10991 | |
GRM5 | GeneProduct | ncbigene:2915 | |
SLC7A10 | GeneProduct | ncbigene:56301 | |
SLC2A1 | GeneProduct | ncbigene:6513 | |
SLC2A3 | GeneProduct | ncbigene:6515 | |
CNTF | GeneProduct | ncbigene:1270 | |
TNF | GeneProduct | ncbigene:7124 | |
IL10 | GeneProduct | ncbigene:3586 | |
IGF1 | GeneProduct | ncbigene:3479 | |
SLC1A2 | GeneProduct | ncbigene:6506 | |
SLC1A3 | GeneProduct | ncbigene:6507 | |
IFNGR2 | GeneProduct | ncbigene:3460 | |
IFNGR1 | GeneProduct | ncbigene:3459 | |
CREB1 | GeneProduct | ncbigene:1385 | |
ARC | GeneProduct | ncbigene:23237 | |
BCL2 | GeneProduct | ncbigene:596 | |
FOS | GeneProduct | ncbigene:2353 | |
GS | Protein | uniprot:P15104 |
References
- Neuroprotective strategies for NMDAR-mediated excitotoxicity in Huntington’s Disease. Girling KD, Wang YT. Front Biol [Internet]. 2016 Nov 17;11(6):439–58. Available from: http://dx.doi.org/10.1007/s11515-016-1425-z DOI Scholia
- The human blood-brain barrier glucose transporter (GLUT1) is a glucose transporter of gray matter astrocytes. Morgello S, Uson RR, Schwartz EJ, Haber RS. Glia. 1995 May;14(1):43–54. PubMed Europe PMC Scholia
- Alteration of second messengers during acute cerebral ischemia - adenylate cyclase, cyclic AMP-dependent protein kinase, and cyclic AMP response element binding protein. Tanaka K. Prog Neurobiol. 2001 Oct;65(2):173–207. PubMed Europe PMC Scholia
- How calcium inhibits the magnesium-dependent enzyme human phosphoserine phosphatase. Peeraer Y, Rabijns A, Collet JF, Van Schaftingen E, De Ranter C. Eur J Biochem. 2004 Aug;271(16):3421–7. PubMed Europe PMC Scholia
- Smads keep TABs on inflammation. Seth RB, Chen ZJ. Nat Immunol. 2007 May;8(5):477–8. PubMed Europe PMC Scholia
- Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia, a critical review and meta-analysis. Tsai GE, Lin PY. Curr Pharm Des. 2010;16(5):522–37. PubMed Europe PMC Scholia
- Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Hardingham GE, Bading H. Nat Rev Neurosci. 2010 Oct;11(10):682–96. PubMed Europe PMC Scholia
- Long-term potentiation and long-term depression: a clinical perspective. Bliss TVP, Cooke SF. Clinics (Sao Paulo). 2011;66 Suppl 1(Suppl 1):3–17. PubMed Europe PMC Scholia
- Metal toxicity at the synapse: presynaptic, postsynaptic, and long-term effects. Sadiq S, Ghazala Z, Chowdhury A, Büsselberg D. J Toxicol. 2012;2012:132671. PubMed Europe PMC Scholia
- IL-4 in the brain: a cytokine to remember. Gadani SP, Cronk JC, Norris GT, Kipnis J. J Immunol. 2012 Nov 1;189(9):4213–9. PubMed Europe PMC Scholia
- D-serine as a gliotransmitter and its roles in brain development and disease. Van Horn MR, Sild M, Ruthazer ES. Front Cell Neurosci. 2013 Apr 23;7:39. PubMed Europe PMC Scholia
- Metabotropic glutamate receptors for Parkinson’s disease therapy. Gasparini F, Di Paolo T, Gomez-Mancilla B. Parkinsons Dis. 2013;2013:196028. PubMed Europe PMC Scholia
- Extrasynaptic NMDA receptor involvement in central nervous system disorders. Parsons MP, Raymond LA. Neuron. 2014 Apr 16;82(2):279–93. PubMed Europe PMC Scholia
- When astrocytes become harmful: functional and inflammatory responses that contribute to Alzheimer’s disease. Avila-Muñoz E, Arias C. Ageing Res Rev. 2014 Nov;18:29–40. PubMed Europe PMC Scholia
- Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases. Tang Y, Le W. Mol Neurobiol. 2016 Mar;53(2):1181–94. PubMed Europe PMC Scholia
- DISC1, astrocytes and neuronal maturation: a possible mechanistic link with implications for mental disorders. Xia M, Zhu S, Shevelkin A, Ross CA, Pletnikov M. J Neurochem. 2016 Aug;138(4):518–24. PubMed Europe PMC Scholia
- Astrocytes: Key Regulators of Neuroinflammation. Colombo E, Farina C. Trends Immunol. 2016 Sep;37(9):608–20. PubMed Europe PMC Scholia
- Role of Atypical Chemokine Receptors in Microglial Activation and Polarization. Salvi V, Sozio F, Sozzani S, Del Prete A. Front Aging Neurosci. 2017 May 26;9:148. PubMed Europe PMC Scholia
- D-serine released by astrocytes in brainstem regulates breathing response to CO2 levels. Beltrán-Castillo S, Olivares MJ, Contreras RA, Zúñiga G, Llona I, von Bernhardi R, et al. Nat Commun. 2017 Oct 10;8(1):838. PubMed Europe PMC Scholia
- Glutamatergic synaptic plasticity and dysfunction in Alzheimer disease: Emerging mechanisms. Benarroch EE. Neurology. 2018 Jul 17;91(3):125–32. PubMed Europe PMC Scholia
- Astrocytic Regulation of Glutamate Transmission in Schizophrenia. Mei YY, Wu DC, Zhou N. Front Psychiatry. 2018 Nov 6;9:544. PubMed Europe PMC Scholia
- Deleterious Alteration of Glia in the Brain of Alzheimer’s Disease. Kim E, Otgontenger U, Jamsranjav A, Kim SS. Int J Mol Sci. 2020 Sep 12;21(18):6676. PubMed Europe PMC Scholia
- The Dual Role of Glutamatergic Neurotransmission in Alzheimer’s Disease: From Pathophysiology to Pharmacotherapy. Bukke VN, Archana M, Villani R, Romano AD, Wawrzyniak A, Balawender K, et al. Int J Mol Sci. 2020 Oct 9;21(20):7452. PubMed Europe PMC Scholia
- The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation. Comer AL, Carrier M, Tremblay MÈ, Cruz-Martín A. Front Cell Neurosci. 2020 Aug 27;14:274. PubMed Europe PMC Scholia
- Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Kwon HS, Koh SH. Transl Neurodegener. 2020 Nov 26;9(1):42. PubMed Europe PMC Scholia
- Astrocytes: a double-edged sword in neurodegenerative diseases. Ding ZB, Song LJ, Wang Q, Kumar G, Yan YQ, Ma CG. Neural Regen Res. 2021 Sep;16(9):1702–10. PubMed Europe PMC Scholia
- Metabolism of Amino Acids in Cancer. Wei Z, Liu X, Cheng C, Yu W, Yi P. Front Cell Dev Biol. 2021 Jan 12;8:603837. PubMed Europe PMC Scholia