From postsynaptic neurons to astrocytes: the link between glutamate metabolism, Alzheimer’s disease and Parkinson’s disease
Abstract
Glutamate is not only the main excitatory neurotransmitter of the human central nervous system, but also a potent neurotoxin. Therefore, maintaining low-dose, non-toxic extracellular glutamate concentrations between synapses to ensure the reliability of synaptic transmission is essential for maintaining normal physiological functions of neurons. More and more studies have confirmed that the specific pathogenesis of central nervous system diseases (such as Alzheimer’s disease) caused by neuronal damage or death due to abnormal inter-synaptic glutamate concentration may be related to the abnormal function of excitatory amino acid transporter proteins and glutamine synthetase on astrocytes, and that the abnormal expression and function of the above two proteins may be related to the transcription, translation, and even modification of both by the process of transcription, translation, and even modification of astrocytes. oxidative stress, and inflammatory responses occurring in astrocytes during their transcription, translation and even modification. Therefore, in this review, we mainly discuss the relationship between glutamate metabolism (from postsynaptic neurons to astrocytes), Alzheimer’s disease and Parkinson’s disease in recent years.
Funding source: High-level talents training Program of traditional Chinese Medicine in Shandong Province
Funding source: Central Nervous System Drug Key Laboratory of Sichuan Province
Funding source: Joint Innovation Team for Clinical & Basic Research
Award Identifier / Grant number: 202401
Funding source: The Second Affiliated Hospital of Shandong First Medical University
Funding source: National Natural Science Foundation of China
Award Identifier / Grant number: 82274235
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Research ethics: Not applicable.
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Informed consent: Not applicable.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission. Fu-Wang Liu and Xue-Rui Zhang conceived and wrote the manuscript, Yi-Fan Cong drew figures and participated in the writing, Yan-Man Liu participated in the writing, Han-Ting Zhang reviewed the manuscript, and Xue-Qin Hou reviewed and edited the manuscript.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: The authors state no conflict of interest.
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Research funding: This work was supported by the National Natural Science Foundation of China (82274235), the Central Nervous System Drug Key Laboratory of Sichuan Province (240022—01SZ), Joint Innovation Team for Clinical & Basic Research (202401), High-level talents training Program of traditional Chinese Medicine in Shandong Province, and The Second Affiliated Hospital of Shandong First Medical University.
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Data availability: Not applicable.
References
Abdul, H.M., Sama, M.A., Furman, J.L., Mathis, D.M., Beckett, T.L., Weidner, A.M., Patel, E.S., Baig, I., Murphy, M.P., LeVine, H.3rd, et al.. (2009). Cognitive decline in Alzheimer’s disease is associated with selective changes in calcineurin/NFAT signaling. J. Neurosci. 29: 12957–12969, https://doi.org/10.1523/jneurosci.1064-09.2009.Search in Google Scholar
Ahmed, I., Bose, S.K., Pavese, N., Ramlackhansingh, A., Turkheimer, F., Hotton, G., Hammers, A., and Brooks, D.J. (2011). Glutamate NMDA receptor dysregulation in Parkinson’s disease with dyskinesias. Brain 134: 979–986, https://doi.org/10.1093/brain/awr028.Search in Google Scholar PubMed
Amitai, N. and Markou, A. (2010). Effects of metabotropic glutamate receptor 2/3 agonism and antagonism on schizophrenia-like cognitive deficits induced by phencyclidine in rats. Eur. J. Pharmacol. 639: 67–80, https://doi.org/10.1016/j.ejphar.2009.12.040.Search in Google Scholar PubMed PubMed Central
Assous, M., Had-Aissouni, L., Gubellini, P., Melon, C., Nafia, I., Salin, P., Kerkerian-Le-Goff, L., and Kachidian, P. (2014). Progressive Parkinsonism by acute dysfunction of excitatory amino acid transporters in the rat substantia nigra. Neurobiol. Dis. 65: 69–81, https://doi.org/10.1016/j.nbd.2014.01.011.Search in Google Scholar PubMed
Back, M.K., Ruggieri, S., Jacobi, E., and von Engelhardt, J. (2021). Amyloid beta-mediated changes in synaptic function and spine number of neocortical neurons depend on NMDA receptors. Int. J. Mol. Sci. 22: 6298, https://doi.org/10.3390/ijms22126298.Search in Google Scholar PubMed PubMed Central
Bao, X.Q., Kong, X.C., Kong, L.B., Wu, L.Y., Sun, H., and Zhang, D. (2014). Squamosamide derivative FLZ protected dopaminergic neuron by activating Akt signaling pathway in 6-OHDA-induced in vivo and in vitro Parkinson’s disease models. Brain Res. 1547: 49–57, https://doi.org/10.1016/j.brainres.2013.12.026.Search in Google Scholar PubMed
Barthet, G., Moreira-de-Sá, A., Zhang, P., Deforges, S., Castanheira, J., Gorlewicz, A., and Mulle, C. (2022). Presenilin and APP regulate synaptic kainate receptors. J. Neurosci. 42: 9253–9262, https://doi.org/10.1523/jneurosci.0297-22.2022.Search in Google Scholar PubMed PubMed Central
Bauer, D., Haroutunian, V., Meador-Woodruff, J.H., and McCullumsmith, R.E. (2010). Abnormal glycosylation of EAAT1 and EAAT2 in prefrontal cortex of elderly patients with schizophrenia. Schizophr Res 117: 92–98, https://doi.org/10.1016/j.schres.2009.07.025.Search in Google Scholar PubMed PubMed Central
Brocke, K.S., Staufner, C., Luksch, H., Geiger, K.D., Stepulak, A., Marzahn, J., Schackert, G., Temme, A., and Ikonomidou, C. (2010). Glutamate receptors in pediatric tumors of the central nervous system. Cancer Biol. Ther. 9: 455–468, https://doi.org/10.4161/cbt.9.6.10898.Search in Google Scholar PubMed
Butterfield, D.A., Poon, H.F., St Clair, D., Keller, J.N., Pierce, W.M., Klein, J.B., and Markesbery, W.R. (2006). Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer’s disease. Neurobiol. Dis. 22: 223–232, https://doi.org/10.1016/j.nbd.2005.11.002.Search in Google Scholar PubMed
Campolo, N., Mastrogiovanni, M., Mariotti, M., Issoglio, F.M., Estrin, D., Hägglund, P., Grune, T., Davies, M.J., Bartesaghi, S., and Radi, R. (2023). Multiple oxidative post-translational modifications of human glutamine synthetase mediate peroxynitrite-dependent enzyme inactivation and aggregation. J. Biol. Chem. 299: 102941, https://doi.org/10.1016/j.jbc.2023.102941.Search in Google Scholar PubMed PubMed Central
Chakrabarti, R. (1998). Transcriptional regulation of the rat glutamine synthetase gene by tumor necrosis factor-alpha. Eur. J. Biochem. 254: 70–74, https://doi.org/10.1046/j.1432-1327.1998.2540070.x.Search in Google Scholar PubMed
Chen, T.S., Huang, T.H., Lai, M.C., and Huang, C.W. (2023). The role of glutamate receptors in epilepsy. Biomedicines 11: 783, https://doi.org/10.3390/biomedicines11030783.Search in Google Scholar PubMed PubMed Central
Chen, T.Y., Chen, Y.R., Hsu, M.L., Liao, Y.T., Wu, C.H., Yao, C.A., Yang, W.C., Lin, W., and Lin, Y. (2024). Homoplantaginin antagonizes N-Methyl-d-aspartate receptor and extracellular signal-regulated kinase signaling in Aβ oligomers-induced neuropathology/toxicity. J. Agric. Food Chem. 72: 28294–28304, https://doi.org/10.1021/acs.jafc.4c07659.Search in Google Scholar PubMed
Chen, Y., Yang, W., Li, X., Li, X., Yang, H., Xu, Z., and Yu, S. (2015). α-Synuclein-induced internalization of NMDA receptors in hippocampal neurons is associated with reduced inward current and Ca(2+) influx upon NMDA stimulation. Neuroscience. 300: 297–306, https://doi.org/10.1016/j.neuroscience.2015.05.035.Search in Google Scholar PubMed
Chung, E.K., Chen, L.W., Chan, Y.S., and Yung, K.K. (2008). Downregulation of glial glutamate transporters after dopamine denervation in the striatum of 6-hydroxydopamine-lesioned rats. J. Comp. Neurol. 511: 421–437, https://doi.org/10.1002/cne.21852.Search in Google Scholar PubMed
Coombs, I.D. and Cull-Candy, S.G. (2021). Single-channel mechanisms underlying the function, diversity and plasticity of AMPA receptors. Neuropharmacology 198: 108781, https://doi.org/10.1016/j.neuropharm.2021.108781.Search in Google Scholar PubMed
Cramb, K.M.L., Beccano-Kelly, D., Cragg, S.J., and Wade-Martins, R. (2023). Impaired dopamine release in Parkinson’s disease. Brain 146: 3117–3132, https://doi.org/10.1093/brain/awad064.Search in Google Scholar PubMed PubMed Central
da Silva, R.A., Roda, V.M.P., Akamine, P.S., da Silva, D.S., Siqueira, P.V., Matsuda, M., and Hamassaki, D.E. (2023). Blockade of the TGF-β pathway by galunisertib inhibits the glial-mesenchymal transition in Müller glial cells. Exp. Eye Res. 226: 109336, https://doi.org/10.1016/j.exer.2022.109336.Search in Google Scholar PubMed
Dąbrowska, K., Albrecht, J., and Zielińska, M. (2018). Protein kinase C-mediated impairment of glutamine outward transport and SN1 transporter distribution by ammonia in mouse cortical astrocytes. Neurochem. Int. 118: 225–232, https://doi.org/10.1016/j.neuint.2018.07.001.Search in Google Scholar PubMed
Escamilla, S., Badillos, R., Comella, J.X., Solé, M., Pérez-Otaño, I., Mut, J.V.S., Sáez-Valero, J., and Cuchillo-Ibáñez, I. (2024). Synaptic and extrasynaptic distribution of NMDA receptors in the cortex of Alzheimer’s disease patients. Alzheimers Dement 20: 8231–8245, https://doi.org/10.1002/alz.14125.Search in Google Scholar PubMed PubMed Central
Farca Luna, A.J., Perier, M., and Seugnet, L. (2017). Amyloid precursor protein in Drosophila glia regulates sleep and genes involved in glutamate recycling. J. Neurosci. 37: 4289–4300, https://doi.org/10.1523/jneurosci.2826-16.2017.Search in Google Scholar PubMed PubMed Central
Feng, Z.J., Zhang, X., and Chergui, K. (2014). Allosteric modulation of NMDA receptors alters neurotransmission in the striatum of a mouse model of Parkinson’s disease. Exp. Neurol. 255: 154–160, https://doi.org/10.1016/j.expneurol.2014.03.001.Search in Google Scholar PubMed
Ferrer, I., García, M.A., González, I.L., Lucena, D.D., Villalonga, A.R., Tech, M.C., Llorens, F., Garcia-Esparcia, P., Martinez-Maldonado, A., Mendez, M.F., et al.. (2018). Aging-related tau astrogliopathy (ARTAG): not only tau phosphorylation in astrocytes. Brain Pathol. 28: 965–985, https://doi.org/10.1111/bpa.12593.Search in Google Scholar PubMed PubMed Central
Gabrielli, M., Prada, I., Joshi, P., Falcicchia, C., D’Arrigo, G., Rutigliano, G., Battocchio, E., Zenatelli, R., Tozzi, F., Radeghieri, A., et al.. (2022). Microglial large extracellular vesicles propagate early synaptic dysfunction in Alzheimer’s disease. Brain 145: 2849–2868, https://doi.org/10.1093/brain/awac083.Search in Google Scholar PubMed PubMed Central
Gautam, D., Naik, U.P., Naik, M.U., Yadav, S.K., Chaurasia, R.N., and Dash, D. (2023). Glutamate receptor dysregulation and platelet glutamate dynamics in Alzheimer’s and Parkinson’s diseases: insights into current medications. Biomolecules 13: 1609, https://doi.org/10.3390/biom13111609.Search in Google Scholar PubMed PubMed Central
Ge, Y. and Wang, Y.T. (2021). GluA1-homomeric AMPA receptor in synaptic plasticity and neurological diseases. Neuropharmacology 197: 108708, https://doi.org/10.1016/j.neuropharm.2021.108708.Search in Google Scholar PubMed
Gebhardt, F.M., Mitrovic, A.D., Gilbert, D.F., Vandenberg, R.J., Lynch, J.W., and Dodd, P.R. (2010). Exon-skipping splice variants of excitatory amino acid transporter-2 (EAAT2) form heteromeric complexes with full-length EAAT2. J. Biol. Chem. 285: 31313–31324, https://doi.org/10.1074/jbc.m110.153494.Search in Google Scholar
Ghosh, M., Yang, Y., Rothstein, J.D., and Robinson, M.B. (2011). Nuclear factor-κB contributes to neuron-dependent induction of glutamate transporter-1 expression in astrocytes. J. Neurosci. 31: 9159–9169, https://doi.org/10.1523/jneurosci.0302-11.2011.Search in Google Scholar PubMed PubMed Central
Guntupalli, S., Park, P., Han, D.H., Zhang, L., Yong, X.L.H., Ringuet, M., Blackmore, D.G., Jhaveri, D.J., Koentgen, F., Widagdo, J., et al.. (2023). Ubiquitination of the GluA1 subunit of AMPA receptors is required for synaptic plasticity, memory, and cognitive flexibility. J. Neurosci. 43: 5448–5457, https://doi.org/10.1523/jneurosci.1542-22.2023.Search in Google Scholar PubMed PubMed Central
Han, X., Yang, L., Du, H., Sun, Q., Wang, X., Cong, L., Liu, X., Yin, L., Li, S., and Du, Y. (2016). Insulin attenuates beta-amyloid-associated insulin/Akt/EAAT signaling perturbations in human astrocytes. Cell Mol Neurobiol. 36: 851–864, https://doi.org/10.1007/s10571-015-0268-5.Search in Google Scholar PubMed PubMed Central
Henderson, J.L., Reynolds, J.D., Dexter, F., Atkins, B., Hrdy, J., Poduska, D., and Penning, D.H. (1998). Chronic hypoxemia causes extracellular glutamate concentration to increase in the cerebral cortex of the near-term fetal sheep. Brain Res. Dev. Brain Res. 105: 287–293, https://doi.org/10.1016/s0165-3806(97)00192-2.Search in Google Scholar PubMed
Herbst, E.A. and Holloway, G.P. (2016). Exercise increases mitochondrial glutamate oxidation in the mouse cerebral cortex. Appl. Physiol. Nutr. Metab. 41: 799–801, https://doi.org/10.1139/apnm-2016-0033.Search in Google Scholar PubMed
Hodgson, N., Trivedi, M., Muratore, C., Li, S., and Deth, R. (2013). Soluble oligomers of amyloid-β cause changes in redox state, DNA methylation, and gene transcription by inhibiting EAAT3 mediated cysteine uptake. J. Alzheimers Dis. 36: 197–209, https://doi.org/10.3233/jad-130101.Search in Google Scholar PubMed
Hou, Q., Hu, W., Peterson, L., Gilbert, J., Liu, R., and Man, H.Y. (2024). SIK1 downregulates synaptic AMPA receptors and contributes to cognitive defects in Alzheimer’s disease. Mol. Neurobiol. 61: 10365–10380, https://doi.org/10.1007/s12035-024-04177-6.Search in Google Scholar PubMed
Huang, S., Tong, H., Lei, M., Zhou, M., Guo, W., Li, G., Tang, X., Li, Z., Mo, M., Zhang, X., et al.. (2018). Astrocytic glutamatergic transporters are involved in Aβ-induced synaptic dysfunction. Brain Res. 1678: 129–137, https://doi.org/10.1016/j.brainres.2017.10.011.Search in Google Scholar PubMed
Huang, T.L. and O’Banion, M.K. (1998). Interleukin-1 beta and tumor necrosis factor-alpha suppress dexamethasone induction of glutamine synthetase in primary mouse astrocytes. J. Neurochem. 71: 1436–1442, https://doi.org/10.1046/j.1471-4159.1998.71041436.x.Search in Google Scholar PubMed
Iemolo, A., De Risi, M., Giordano, N., Torromino, G., Somma, C., Cavezza, D., Colucci, M., Mancini, M., de Iure, A., Granata, R., et al.. (2023). Synaptic mechanisms underlying onset and progression of memory deficits caused by hippocampal and midbrain synucleinopathy. NPJ Parkinson. Dis. 9: 92, https://doi.org/10.1038/s41531-023-00520-1.Search in Google Scholar PubMed PubMed Central
Iovino, L., Giusti, V., Pischedda, F., Giusto, E., Plotegher, N., Marte, A., Battisti, I., Di Iacovo, A., Marku, A., Piccoli, G., et al.. (2022). Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson’s disease. Acta Neuropathol. 144: 81–106, https://doi.org/10.1007/s00401-022-02437-0.Search in Google Scholar PubMed PubMed Central
Iovino, L., Tremblay, M.E., and Civiero, L. (2020). Glutamate-induced excitotoxicity in Parkinson’s disease: the role of glial cells. J. Pharmacol. Sci. 144: 151–164, https://doi.org/10.1016/j.jphs.2020.07.011.Search in Google Scholar PubMed
Jacob, C.P., Koutsilieri, E., Bartl, J., Neuen-Jacob, E., Arzberger, T., Zander, N., Ravid, R., Roggendorf, W., Riederer, P., and Grünblatt, E. (2007). Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer’s disease. J. Alzheimers Dis. 11: 97–116, https://doi.org/10.3233/jad-2007-11113.Search in Google Scholar PubMed
Jh, Y.Y., Waldvogel, H.J., Rl, M.F., and Kwakowsky, A. (2022). iGluR expression in the hippocampal formation, entorhinal cortex, and superior temporal gyrus in Alzheimer’s disease. Neural. Regen Res. 17: 2197–2199, https://doi.org/10.4103/1673-5374.335804.Search in Google Scholar PubMed PubMed Central
Jing, X.Z., Yuan, X.Z., Luo, X., Zhang, S.Y., and Wang, X.P. (2023). An update on nondopaminergic treatments for motor and non-motor symptoms of Parkinson’s disease. Curr. Neuropharmacol. 21: 1806–1826, https://doi.org/10.2174/1570159x20666220222150811.Search in Google Scholar PubMed PubMed Central
Kalandadze, A., Wu, Y., Fournier, K., and Robinson, M.B. (2004). Identification of motifs involved in endoplasmic reticulum retention-forward trafficking of the GLT-1 subtype of glutamate transporter. J. Neurosci. 24: 5183–5192, https://doi.org/10.1523/jneurosci.0839-04.2004.Search in Google Scholar
Kamiya, H. (2002). Kainate receptor-dependent presynaptic modulation and plasticity. Neurosci. Res. 42: 1–6, https://doi.org/10.1016/s0168-0102(01)00303-0.Search in Google Scholar PubMed
Kamphuis, W., Middeldorp, J., Kooijman, L., Sluijs, J.A., Kooi, E.J., Moeton, M., Freriks, M., Mizee, M.R., and Hol, E.M. (2014). Glial fibrillary acidic protein isoform expression in plaque related astrogliosis in Alzheimer’s disease. Neurobiol. Aging. 35: 492–510, https://doi.org/10.1016/j.neurobiolaging.2013.09.035.Search in Google Scholar PubMed
Karki, P., Kim, C., Smith, K., Son, D.S., Aschner, M., and Lee, E. (2015). Transcriptional regulation of the astrocytic excitatory amino acid transporter 1 (EAAT1) via NF-κB and yin yang 1 (YY1). J. Biol. Chem. 290: 23725–23737, https://doi.org/10.1074/jbc.m115.649327.Search in Google Scholar PubMed PubMed Central
Karki, P., Webb, A., Smith, K., Lee, K., Son, D.S., Aschner, M., and Lee, E. (2013). cAMP response element-binding protein (CREB) and nuclear factor κB mediate the tamoxifen-induced up-regulation of glutamate transporter 1 (GLT-1) in rat astrocytes. J. Biol. Chem. 288: 28975–28986, https://doi.org/10.1074/jbc.m113.483826.Search in Google Scholar
Katsipis, G., Tzekaki, E.E., Tsolaki, M., and Pantazaki, A.A. (2021). Salivary GFAP as a potential biomarker for diagnosis of mild cognitive impairment and Alzheimer’s disease and its correlation with neuroinflammation and apoptosis. J. Neuroimmunol. 361: 577744, https://doi.org/10.1016/j.jneuroim.2021.577744.Search in Google Scholar PubMed
Kim, Y.K. and Na, K.S. (2016). Role of glutamate receptors and glial cells in the pathophysiology of treatment-resistant depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 70: 117–126, https://doi.org/10.1016/j.pnpbp.2016.03.009.Search in Google Scholar PubMed
Knorpp, T., Robinson, S.R., Crack, P.J., and Dringen, R. (2006). Glutathione peroxidase-1 contributes to the protection of glutamine synthetase in astrocytes during oxidative stress. J. Neural. Transm. (Vienna) 113: 1145–1155, https://doi.org/10.1007/s00702-005-0389-y.Search in Google Scholar PubMed
Kolacheva, A., Bannikova, A., Pavlova, E., Bogdanov, V., and Ugrumov, M. (2022). Modeling of the progressive degradation of the nigrostriatal dopaminergic system in mice to study the mechanisms of neurodegeneration and neuroplasticity in Parkinson’s disease. Int. J. Mol. Sci. 24: 683, https://doi.org/10.3390/ijms24010683.Search in Google Scholar PubMed PubMed Central
Kosenko, E., Llansola, M., Montoliu, C., Monfort, P., Rodrigo, R., Hernandez-Viadel, M., Erceg, S., Sánchez-Perez, A.M., and Felipo, V. (2003). Glutamine synthetase activity and glutamine content in brain: modulation by NMDA receptors and nitric oxide. Neurochem. Int. 43: 493–499, https://doi.org/10.1016/s0197-0186(03)00039-1.Search in Google Scholar PubMed
Kostic, M., Zivkovic, N., Cvetanovic, A., Stojanovic, I., and Colic, M. (2017). IL-17 signalling in astrocytes promotes glutamate excitotoxicity: indications for the link between inflammatory and neurodegenerative events in multiple sclerosis. Mult. Scler. Relat. Disord. 11: 12–17, https://doi.org/10.1016/j.msard.2016.11.006.Search in Google Scholar PubMed
Lee, D.W., Woo, C.W., Woo, D.C., Kim, J.K., Kim, K.W., and Lee, D.H. (2020). Regional mapping of brain glutamate distributions using glutamate-weighted chemical exchange saturation transfer imaging. Diagn. (Basel) 10: 571, https://doi.org/10.3390/diagnostics10080571.Search in Google Scholar PubMed PubMed Central
Lehmann, C., Bette, S., and Engele, J. (2009). High extracellular glutamate modulates expression of glutamate transporters and glutamine synthetase in cultured astrocytes. Brain Res. 1297: 1–8, https://doi.org/10.1016/j.brainres.2009.08.070.Search in Google Scholar PubMed
Li, X., Wang, W., Yan, J., and Zeng, F. (2021). Glutamic acid transporters: targets for neuroprotective therapies in Parkinson’s disease. Front Neurosci. 15: 678154, https://doi.org/10.3389/fnins.2021.678154.Search in Google Scholar PubMed PubMed Central
Lu, K., Li, C., Liu, J., Wang, J., Li, Y., He, B., Li, J., Zhang, X., Wei, M., Tian, Y., et al.. (2023). Impairments in endogenous AMPA receptor dynamics correlates with learning deficits in Alzheimer’s disease model mice. Proc. Natl. Acad. Sci. U. S. A. 120, https://doi.org/10.1073/pnas.2303878120.Search in Google Scholar PubMed PubMed Central
Martinez, T.P., Larsen, M.E., Sullivan, E., Woolfrey, K.M., and Dell’Acqua, M.L. (2024). Amyloid-β-induced dendritic spine elimination requires Ca(2+)-permeable AMPA receptors, AKAP-Calcineurin-NFAT signaling, and the NFAT target gene Mdm2. eNeuro 11: 0175–223, https://doi.org/10.1523/eneuro.0175-23.2024.Search in Google Scholar
Meng, X., Zhong, J., Zeng, C., Yung, K.K.L., Zhang, X., Wu, X., and Qu, S. (2021). MiR-30a-5p regulates GLT-1 function via a PKCα-mediated ubiquitin degradation pathway in a mouse model of Parkinson’s disease. ACS Chem. Neurosci. 12: 1578–1592, https://doi.org/10.1021/acschemneuro.1c00076.Search in Google Scholar PubMed
Milanese, M., Zappettini, S., Onofri, F., Musazzi, L., Tardito, D., Bonifacino, T., Messa, M., Racagni, G., Usai, C., Benfenati, F., et al.. (2011). Abnormal exocytotic release of glutamate in a mouse model of amyotrophic lateral sclerosis. J. Neurochem. 116: 1028–1042, https://doi.org/10.1111/j.1471-4159.2010.07155.x.Search in Google Scholar PubMed
Moriguchi, S., Han, F., Shioda, N., Yamamoto, Y., Nakajima, T., Nakagawasai, O., Tadano, T., Yeh, J.Z., Narahashi, T., and Fukunaga, K. (2009). Nefiracetam activation of CaM kinase II and protein kinase C mediated by NMDA and metabotropic glutamate receptors in olfactory bulbectomized mice. J. Neurochem. 110: 170–181, https://doi.org/10.1111/j.1471-4159.2009.06122.x.Search in Google Scholar PubMed
Murray, T.E., Richards, C.M., Robert-Gostlin, V.N., Bernath, A.K., Lindhout, I.A., and Klegeris, A. (2022). Potential neurotoxic activity of diverse molecules released by astrocytes. Brain Res. Bull. 189: 80–101, https://doi.org/10.1016/j.brainresbull.2022.08.015.Search in Google Scholar PubMed
Nafia, I., Re, D.B., Masmejean, F., Melon, C., Kachidian, P., Kerkerian-Le Goff, L., Nieoullon, A., and Had-Aissouni, L. (2008). Preferential vulnerability of mesencephalic dopamine neurons to glutamate transporter dysfunction. J. Neurochem. 105: 484–496, https://doi.org/10.1111/j.1471-4159.2007.05146.x.Search in Google Scholar PubMed
Navarria, L., Zaltieri, M., Longhena, F., Spillantini, M.G., Missale, C., Spano, P., and Bellucci, A. (2015). Alpha-synuclein modulates NR2B-containing NMDA receptors and decreases their levels after rotenone exposure. Neurochem. Int. 85-86: 14–23, https://doi.org/10.1016/j.neuint.2015.03.008.Search in Google Scholar PubMed
O’Day, D.H. (2023). Calmodulin and amyloid beta as coregulators of critical events during the onset and progression of Alzheimer’s disease. Int. J. Mol. Sci. 24: 1393, https://doi.org/10.3390/ijms24021393.Search in Google Scholar PubMed PubMed Central
Otero-Garcia, M., Mahajani, S.U., Wakhloo, D., Tang, W., Xue, Y.Q., Morabito, S., Pan, J., Oberhauser, J., Madira, A.E., Shakouri, T., et al.. (2022). Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease. Neuron 110: 2929–2948.e2928, https://doi.org/10.1016/j.neuron.2022.06.021.Search in Google Scholar PubMed PubMed Central
Pan, J., Ma, N., Zhong, J., Yu, B., Wan, J., and Zhang, W. (2021). Age-associated changes in microglia and astrocytes ameliorate blood-brain barrier dysfunction. Mol. Ther. Nucleic. Acids 26: 970–986, https://doi.org/10.1016/j.omtn.2021.08.030.Search in Google Scholar PubMed PubMed Central
Perea, G., Navarrete, M., and Araque, A. (2009). Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 32: 421–431, https://doi.org/10.1016/j.tins.2009.05.001.Search in Google Scholar PubMed
Perszyk, R.E., Zheng, Z., Banke, T.G., Zhang, J., Xie, L., McDaniel, M.J., Katzman, B.M., Pelly, S.C., Yuan, H., Liotta, D.C., et al.. (2021). The negative allosteric modulator EU1794-4 reduces single-channel conductance and Ca(2+) permeability of GluN1/GluN2A N-Methyl-d-Aspartate receptors. Mol. Pharmacol. 99: 399–411, https://doi.org/10.1124/molpharm.120.000218.Search in Google Scholar PubMed PubMed Central
Piccirillo, S., Magi, S., Preziuso, A., Castaldo, P., Amoroso, S., and Lariccia, V. (2020). Gateways for glutamate neuroprotection in Parkinson’s disease (PD): essential role of EAAT3 and NCX1 revealed in an in vitro model of PD. Cells 9: 2037, https://doi.org/10.3390/cells9092037.Search in Google Scholar PubMed PubMed Central
Poletti, S., Radaelli, D., Bosia, M., Buonocore, M., Pirovano, A., Lorenzi, C., Cavallaro, R., Smeraldi, E., and Benedetti, F. (2014). Effect of glutamate transporter EAAT2 gene variants and gray matter deficits on working memory in schizophrenia. Eur. Psychiatry 29: 219–225, https://doi.org/10.1016/j.eurpsy.2013.07.003.Search in Google Scholar PubMed
Price, B.R., Johnson, L.A., and Norris, C.M. (2021). Reactive astrocytes: the nexus of pathological and clinical hallmarks of Alzheimer’s disease. Ageing Res. Rev. 68: 101335, https://doi.org/10.1016/j.arr.2021.101335.Search in Google Scholar PubMed PubMed Central
Prinkey, K., Thompson, E., Saikia, J., Cid, T., and Dore, K. (2024). Fluorescence lifetime imaging of AMPA receptor endocytosis in living neurons: effects of Aβ and PP1. Front Mol. Neurosci. 17: 1409401, https://doi.org/10.3389/fnmol.2024.1409401.Search in Google Scholar PubMed PubMed Central
Quincozes-Santos, A., Santos, C.L., de Souza Almeida, R.R., da Silva, A., Thomaz, N.K., Costa, N.L.F., Weber, F.B., Schmitz, I., Medeiros, L.S., Medeiros, L., et al.. (2021). Gliotoxicity and glioprotection: the dual role of glial cells. Mol. Neurobiol. 58: 6577–6592, https://doi.org/10.1007/s12035-021-02574-9.Search in Google Scholar PubMed PubMed Central
Reiner, A. and Levitz, J. (2018). Glutamatergic signaling in the central nervous system: ionotropic and metabotropic receptors in concert. Neuron 98: 1080–1098, https://doi.org/10.1016/j.neuron.2018.05.018.Search in Google Scholar PubMed PubMed Central
Rizor, A., Pajarillo, E., Nyarko-Danquah, I., Digman, A., Mooneyham, L., Son, D.S., Aschner, M., and Lee, E. (2021). Manganese-induced reactive oxygen species activate IκB kinase to upregulate YY1 and impair glutamate transporter EAAT2 function in human astrocytes in vitro. Neurotoxicology 86: 94–103, https://doi.org/10.1016/j.neuro.2021.07.004.Search in Google Scholar PubMed PubMed Central
Rizor, A., Pajarillo, E., Son, D.S., Aschner, M., and Lee, E. (2022). Manganese phosphorylates Yin Yang 1 at serine residues to repress EAAT2 in human H4 astrocytes. Toxicol. Lett. 355: 41–46, https://doi.org/10.1016/j.toxlet.2021.11.007.Search in Google Scholar PubMed PubMed Central
Robinson, S.R. (2000). Neuronal expression of glutamine synthetase in Alzheimer’s disease indicates a profound impairment of metabolic interactions with astrocytes. Neurochem. Int. 36: 471–482, https://doi.org/10.1016/s0197-0186(99)00150-3.Search in Google Scholar PubMed
Schwab, K., Chasapopoulou, Z., Frahm, S., Magbagbeolu, M., Cranston, A., Harrington, C.R., Wischik, C.M., Theuring, F., and Riedel, G. (2022). Glutamatergic transmission and receptor expression in the synucleinopathy h-α-synL62 mouse model: effects of hydromethylthionine. Cell Signal 97: 110386, https://doi.org/10.1016/j.cellsig.2022.110386.Search in Google Scholar PubMed
Scott, H.A., Gebhardt, F.M., Mitrovic, A.D., Vandenberg, R.J., and Dodd, P.R. (2011). Glutamate transporter variants reduce glutamate uptake in Alzheimer’s disease. Neurobiol. Aging 32: 553.e551–511, https://doi.org/10.1016/j.neurobiolaging.2010.03.008.Search in Google Scholar PubMed
Sheehan, P.W., Nadarajah, C.J., Kanan, M.F., Patterson, J.N., Novotny, B., Lawrence, J.H., King, M.W., Brase, L., Inman, C.E., Yuede, C.M., et al.. (2023). An astrocyte BMAL1-BAG3 axis protects against alpha-synuclein and tau pathology. Neuron 111: 2383–2398, https://doi.org/10.1016/j.neuron.2023.05.006.Search in Google Scholar PubMed PubMed Central
Shen, L., Chen, C., Yang, A., Chen, Y., Liu, Q., and Ni, J. (2015). Redox proteomics identification of specifically carbonylated proteins in the hippocampi of triple transgenic Alzheimer’s disease mice at its earliest pathological stage. J. Proteom. 123: 101–113, https://doi.org/10.1016/j.jprot.2015.04.005.Search in Google Scholar PubMed
Shen, X. and Xu, G. (2009). Role of IL-1beta on the glutamine synthetase in retinal Müller cells under high glucose conditions. Curr. Eye Res. 34: 727–736, https://doi.org/10.1080/02713680903030875.Search in Google Scholar PubMed
Sheng, L., Stewart, T., Yang, D., Thorland, E., Soltys, D., Aro, P., Khrisat, T., Xie, Z., Li, N., Liu, Z., et al.. (2020). Erythrocytic α-synuclein contained in microvesicles regulates astrocytic glutamate homeostasis: a new perspective on Parkinson’s disease pathogenesis. Acta Neuropathol. Commun. 8: 102, https://doi.org/10.1186/s40478-020-00983-w.Search in Google Scholar PubMed PubMed Central
Sitzia, G., Mantas, I., Zhang, X., Svenningsson, P., and Chergui, K. (2020). NMDA receptors are altered in the substantia nigra pars reticulata and their blockade ameliorates motor deficits in experimental parkinsonism. Neuropharmacology 174: 108136, https://doi.org/10.1016/j.neuropharm.2020.108136.Search in Google Scholar PubMed
Song, X., Gong, Z., Liu, K., Kou, J., Liu, B., and Liu, K. (2020). Baicalin combats glutamate excitotoxicity via protecting glutamine synthetase from ROS-induced 20S proteasomal degradation. Redox Biol. 34: 101559, https://doi.org/10.1016/j.redox.2020.101559.Search in Google Scholar PubMed PubMed Central
Song, Z., Bian, Z., Zhang, Z., Wang, X., Zhu, A., and Zhu, G. (2021). Astrocytic Kir4.1 regulates NMDAR/calpain signaling axis in lipopolysaccharide-induced depression-like behaviors in mice. Toxicol. Appl. Pharmacol. 429: 115711, https://doi.org/10.1016/j.taap.2021.115711.Search in Google Scholar PubMed
Srivastava, A., Das, B., Yao, A.Y., and Yan, R. (2020). Metabotropic glutamate receptors in Alzheimer’s disease synaptic dysfunction: therapeutic opportunities and hope for the future. J. Alzheimers Dis. 78: 1345–1361, https://doi.org/10.3233/jad-201146.Search in Google Scholar
Stepan, J., Heinz, D.E., Dethloff, F., Wiechmann, S., Martinelli, S., Hafner, K., Ebert, T., Junglas, E., Häusl, A.S., Pöhlmann, M.L., et al.. (2024). Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice. Sci. Signal 17: eadj6603, https://doi.org/10.1126/scisignal.adj6603.Search in Google Scholar PubMed
Sun, Y.W., Zhang, L.Y., Gong, S.J., Hu, Y.Y., Zhang, J.G., Xian, X.H., Li, W.B., and Zhang, M. (2021). The p38 MAPK/NF-κB pathway mediates GLT-1 up-regulation during cerebral ischemic preconditioning-induced brain ischemic tolerance in rats. Brain Res. Bull. 175: 224–233, https://doi.org/10.1016/j.brainresbull.2021.07.029.Search in Google Scholar PubMed
Swamy, M., Sirajudeen, K.N., and Chandran, G. (2009). Nitric oxide (NO), citrulline-NO cycle enzymes, glutamine synthetase, and oxidative status in kainic acid-mediated excitotoxicity in rat brain. Drug Chem. Toxicol. 32: 326–331, https://doi.org/10.1080/01480540903130641.Search in Google Scholar PubMed
Talantova, M., Sanz-Blasco, S., Zhang, X., Xia, P., Akhtar, M.W., Okamoto, S., Dziewczapolski, G., Nakamura, T., Cao, G., Pratt, A.E., et al.. (2013). Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc. Natl. Acad. Sci. U. S. A. 110: E2518–E2527, https://doi.org/10.1073/pnas.1306832110.Search in Google Scholar PubMed PubMed Central
Tavalin, S.J. (2024). Familial Alzheimer’s disease mutations in amyloid precursor protein impair calcineurin signaling to NMDA receptors. J. Biol. Chem. 301: 108147, https://doi.org/10.1016/j.jbc.2024.108147.Search in Google Scholar PubMed PubMed Central
Tong, H., Zhang, X., Meng, X., Xu, P., Zou, X., and Qu, S. (2017). Amyloid-beta peptide decreases expression and function of glutamate transporters in nervous system cells. Int. J. Biochem. Cell Biol. 85: 75–84, https://doi.org/10.1016/j.biocel.2017.01.017.Search in Google Scholar PubMed
Tozzi, A., de Iure, A., Bagetta, V., Tantucci, M., Durante, V., Quiroga-Varela, A., Costa, C., Di Filippo, M., Ghiglieri, V., Latagliata, E.C., et al.. (2016). Alpha-synuclein produces early behavioral alterations via striatal cholinergic synaptic dysfunction by interacting with GluN2D N-Methyl-D-Aspartate receptor subunit. Biol. Psychiat. 79: 402–414, https://doi.org/10.1016/j.biopsych.2015.08.013.Search in Google Scholar PubMed
Valdivielso, J.M., Eritja, À., Caus, M., and Bozic, M. (2020). Glutamate-gated NMDA receptors: insights into the function and signaling in the kidney. Biomolecules 10: 1051, https://doi.org/10.3390/biom10071051.Search in Google Scholar PubMed PubMed Central
Vandresen-Filho, S., Martins, W.C., Bertoldo, D.B., Mancini, G., Herculano, B.A., de Bem, A.F., and Tasca, C.I. (2013). Atorvastatin prevents cell damage via modulation of oxidative stress, glutamate uptake and glutamine synthetase activity in hippocampal slices subjected to oxygen/glucose deprivation. Neurochem. Int. 62: 948–955, https://doi.org/10.1016/j.neuint.2013.03.002.Search in Google Scholar PubMed
von Bartheld, C.S., Bahney, J., and Herculano-Houzel, S. (2016). The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J. Comp. Neurol. 524: 3865–3895, https://doi.org/10.1002/cne.24040.Search in Google Scholar PubMed PubMed Central
Voronkov, D.N., Stavrovskaya, A.V., Potapov, I.A., Guschina, A.S., and Olshanskiy, A.S. (2023). Glial reaction in a neuroinflammatory model of Parkinson’s disease. Bull. Exp. Biol. Med. 174: 693–698, https://doi.org/10.1007/s10517-023-05772-8.Search in Google Scholar PubMed
Wang, S., Zhang, H., Geng, B., Xie, Q., Li, W., Deng, Y., Shi, W., Pan, Y., Kang, X., and Wang, J. (2018). 2-arachidonyl glycerol modulates astrocytic glutamine synthetase via p38 and ERK1/2 pathways. J. Neuroinflammation 15: 220, https://doi.org/10.1186/s12974-018-1254-x.Search in Google Scholar PubMed PubMed Central
Watts, J., Fowler, L., Whitton, P.S., and Pearce, B. (2005). Release of arginine, glutamate and glutamine in the hippocampus of freely moving rats: involvement of nitric oxide. Brain Res. Bull. 65: 521–528, https://doi.org/10.1016/j.brainresbull.2005.03.011.Search in Google Scholar PubMed
Wei, L., Chen, C., Ding, L., Mo, M., Zou, J., Lu, Z., Li, H., Wu, H., Dai, Y., Xu, P., et al.. (2019). Wnt1 promotes EAAT2 expression and mediates the protective effects of astrocytes on dopaminergic cells in Parkinson’s disease. Neural. Plast. 2019: 1247276, https://doi.org/10.1155/2019/1247276.Search in Google Scholar PubMed PubMed Central
Xiao, H., Zhou, H., Chen, G., Liu, S., and Li, G. (2007). Interaction between inducible nitric oxide synthase and calmodulin in Ca2+-free and -bound forms. J. Proteome Res. 6: 1426–1429, https://doi.org/10.1021/pr060544l.Search in Google Scholar PubMed
Xu, B., Xu, Z., Deng, Y., Liu, W., Yang, H., and Wei, Y.G. (2013). MK-801 protects against intracellular Ca(2+) overloading and improves N-methyl-D-aspartate receptor expression in cerebral cortex of methylmercury-poisoned rats. J. Mol. Neurosci. 49: 162–171, https://doi.org/10.1007/s12031-012-9926-y.Search in Google Scholar PubMed
Yan, J., Bengtson, C.P., Buchthal, B., Hagenston, A.M., and Bading, H. (2020). Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants. Science 370: eaay3302, https://doi.org/10.1126/science.aay3302.Search in Google Scholar PubMed
Yang, J., Hertz, E., Zhang, X., Leinartaité, L., Lundius, E.G., Li, J., and Svenningsson, P. (2016). Overexpression of α-synuclein simultaneously increases glutamate NMDA receptor phosphorylation and reduces glucocerebrosidase activity. Neurosci. Lett. 611: 51–58, https://doi.org/10.1016/j.neulet.2015.11.023.Search in Google Scholar PubMed
Yang, W., Yu, W., Li, X., Li, X., and Yu, S. (2020). Alpha-synuclein differentially reduces surface expression of N-methyl-d-aspartate receptors in the aging human brain. Neurobiol Aging 90: 24–32, https://doi.org/10.1016/j.neurobiolaging.2020.02.015.Search in Google Scholar PubMed
Yang, X., Gong, R., Qin, L., Bao, Y., Fu, Y., Gao, S., Yang, H., Ni, J., Yuan, T.F., and Lu, W. (2022). Trafficking of NMDA receptors is essential for hippocampal synaptic plasticity and memory consolidation. Cell Rep. 40: 111217, https://doi.org/10.1016/j.celrep.2022.111217.Search in Google Scholar PubMed
Yu, C., Ruan, Y., Sun, X., Chen, C., Shen, T., Liu, C., Qiu, W., Lu, Z., Chan, S.O., and Wang, L. (2023). rTMS ameliorates depression/anxiety-like behaviors in experimental autoimmune encephalitis by inhibiting neurotoxic reactive astrocytes. J. Affect. Disord. 331: 352–361, https://doi.org/10.1016/j.jad.2023.03.069.Search in Google Scholar PubMed
Yu, L., Li, Y., Lv, Y., Gu, B., Cai, J., Liu, Q.S., and Zhao, L. (2024). Treadmill exercise facilitates synaptic plasticity in APP/PS1 mice by regulating hippocampal AMPAR activity. Cells 13: 1608, https://doi.org/10.3390/cells13191608.Search in Google Scholar PubMed PubMed Central
Zhang, T., Musheshe, N., van der Veen, C., Kessels, H.W., Dolga, A., De Deyn, P., Eisel, U., and Schmidt, M. (2023). The expression of Epac2 and GluA3 in an Alzheimer’s disease experimental model and postmortem patient samples. Biomedicines 11: 2096, https://doi.org/10.3390/biomedicines11082096.Search in Google Scholar PubMed PubMed Central
Zhang, T. and Schmidt, M. (2025). Targeting Epac2 and GluA3-containing AMPARs: a novel therapeutic strategy for Alzheimer’s disease. Neural. Regen Res. 20: 3223–3224, https://doi.org/10.4103/nrr.nrr-d-24-00751.Search in Google Scholar PubMed PubMed Central
Zheng, J., Xie, Y., Ren, L., Qi, L., Wu, L., Pan, X., Zhou, J., Chen, Z., and Liu, L. (2021). GLP-1 improves the supportive ability of astrocytes to neurons by promoting aerobic glycolysis in Alzheimer’s disease. Mol. Metab. 47: 101180, https://doi.org/10.1016/j.molmet.2021.101180.Search in Google Scholar PubMed PubMed Central
Zheng, J.Y., Sun, J., Ji, C.M., Shen, L., Chen, Z.J., Xie, P., Sun, Y.Z., and Yu, R.T. (2017). Selective deletion of apolipoprotein E in astrocytes ameliorates the spatial learning and memory deficits in Alzheimer’s disease (APP/PS1) mice by inhibiting TGF-β/Smad2/STAT3 signaling. Neurobiol. Aging 54: 112–132, https://doi.org/10.1016/j.neurobiolaging.2017.03.002.Search in Google Scholar PubMed
Zhou, L. and Duan, J. (2021). The NMDAR GluN1-1a C-terminus binds to CaM and regulates synaptic function. Biochem. Biophys. Res. Commun. 534: 323–329, https://doi.org/10.1016/j.bbrc.2020.11.085.Search in Google Scholar PubMed
Zhu, X., Dong, J., Han, B., Huang, R., Zhang, A., Xia, Z., Chang, H., Chao, J., and Yao, H. (2017). Neuronal nitric oxide synthase contributes to PTZ kindling-induced cognitive impairment and depressive-like behavior. Front Behav. Neurosci. 11: 203, https://doi.org/10.3389/fnbeh.2017.00203.Search in Google Scholar PubMed PubMed Central
Zou, J., Wang, Y.X., Dou, F.F., Lü, H.Z., Ma, Z.W., Lu, P.H., and Xu, X.M. (2010). Glutamine synthetase down-regulation reduces astrocyte protection against glutamate excitotoxicity to neurons. Neurochem. Int. 56: 577–584, https://doi.org/10.1016/j.neuint.2009.12.021.Search in Google Scholar PubMed PubMed Central
Zumkehr, J., Rodriguez-Ortiz, C.J., Cheng, D., Kieu, Z., Wai, T., Hawkins, C., Kilian, J., Lim, S.L., Medeiros, R., and Kitazawa, M. (2015). Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer’s disease. Neurobiol. Aging 36: 2260–2271, https://doi.org/10.1016/j.neurobiolaging.2015.04.005.Search in Google Scholar PubMed
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Articles in the same Issue
- Frontmatter
- Phase-amplitude coupling during auditory steady-state stimulation: a methodological review
- Tool evolution as a prerequisite for consciousness
- Impact of non-alcoholic fatty liver disease on cognition and brain changes: a comprehensive review
- The role of glutamate receptors and transporters in epilepsy: evidence from animal studies
- The neural basis of dialectical thinking: recent advances and future prospects
- Evolving strategies in the diagnosis and treatment of HIV-associated neurocognitive disorders
- From postsynaptic neurons to astrocytes: the link between glutamate metabolism, Alzheimer’s disease and Parkinson’s disease
Articles in the same Issue
- Frontmatter
- Phase-amplitude coupling during auditory steady-state stimulation: a methodological review
- Tool evolution as a prerequisite for consciousness
- Impact of non-alcoholic fatty liver disease on cognition and brain changes: a comprehensive review
- The role of glutamate receptors and transporters in epilepsy: evidence from animal studies
- The neural basis of dialectical thinking: recent advances and future prospects
- Evolving strategies in the diagnosis and treatment of HIV-associated neurocognitive disorders
- From postsynaptic neurons to astrocytes: the link between glutamate metabolism, Alzheimer’s disease and Parkinson’s disease