The DOI matches its Crossref record; 68 of the 70 references it cites were found in a registry or an index.
Deletion of Adenosine A2A Receptors From Astrocytes Disrupts Glutamate Homeostasis Leading to Psychomotor and Cognitive Impairment: Relevance to Schizophrenia
Open accessAbstract
Background Adenosine A2A receptors (A2AR) modulate dopamine and glutamate signaling and thereby may influence some of the psychomotor and cognitive processes associated with schizophrenia. Because astroglial A2AR regulate the availability of glutamate, we hypothesized that they might play an unprecedented role in some of the processes leading to the development of schizophrenia, which we investigated using a mouse line with a selective deletion of A2AR in astrocytes (Gfa2-A2AR knockout [KO] mice].Methods We examined Gfa2-A2AR KO mice for behaviors thought to recapitulate some features of schizophrenia, namely enhanced MK-801 psychomotor response (positive symptoms) and decreased working memory (cognitive symptoms). In addition, we probed for neurochemical alterations in the glutamatergic circuitry, evaluating glutamate uptake and release and the levels of key proteins defining glutamatergic signaling (glutamate transporter-I [GLT-I], N-methyl-D-aspartate receptors [NMDA-R] and α-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPA-R]) to provide a mechanistic understanding of the phenotype encountered.Results We show that Gfa2-A2AR KO mice exhibited enhanced MK-801 psychomotor response and decreased working memory; this was accompanied by a disruption of glutamate homeostasis characterized by aberrant GLT-I activity, increased presynaptic glutamate release, NMDA-R 2B subunit upregulation, and increased internalization of AMPA-R. Accordingly, selective GLT-I inhibition or blockade of GluR1/2 endocytosis prevented the psychomotor and cognitive phenotypes in Gfa2-A2AR KO mice, namely in the nucleus accumbens.Conclusions These results show that the dysfunction of astrocytic A2AR, by controlling GLT-I activity, triggers an astrocyte-to-neuron wave of communication resulting in disrupted glutamate homeostasis, thought to underlie several endophenotypes relevant to schizophrenia.
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“In line with this, transgenic mice lacking the A2A receptor or AD mice treated with an A2A antagonist 101 show increased memory (but see 102 )”
From Astrocyte function from information processing to cognition and cognitive impairment (2019) · cites this paper as [102]
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“93 Notably, depressive behavior is linked to purinergic signaling.”
BackgroundSelf-citationAstrocyte function from information processing to cognition and cognitive impairment
Santello, M., Toni, N., & Volterra, A. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0325-8 · Cited by 737
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Metadata
- Authors
- Matos, M., Shen, H.-Y., Augusto, E., Wang, Y., Wei, C. J., Wang, Y. T., Agostinho, P., Boison, D., Cunha, R. A., & Chen, J.-F.
- Affiliations
- Boston University (US)
- Centro de Neurociências e Biologia Celular (PT)
- Corresponding author
- Chen, Jiang-Fan
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 78
- Issue
- 11
- Pages
- 763-774
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4714966
- OpenAlex
- W2125008776
- Cited by
- 153
- References
- 70
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 12 · 2023: 26 · 2022: 17 · 2021: 8 · 2020: 7 · 2019: 15 · 2018: 18 · 2017: 14 · 2016: 13 · 2015: 5
- FWCI
- 13.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- National Institute of Health (NS041083-11, NS073947, MH083973)
- Defense Advanced Research Projects Agency (09-68-ESR-FP-010, W911NF-10-1-0059)
- Portuguese Foundation for Science and Technology (PTDC/SAU-NSC/122254/2010)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Keywords
- adenosine A2A receptor, astrocytes, glutamate homeostasis, schizophrenia, NMDA receptor NR2B, AMPA receptor internalization, working memory, nucleus accumbens, astrocyte-neuron communication, glutamatergic signaling
- MeSH terms
- Animals, Astrocytes, Cognition Disorders, Disease Models, Animal, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Homeostasis, Kainic Acid, Locomotion, Mice, Inbred C57BL, Mice, Transgenic, Psychomotor Disorders, Pyrimidines, Synaptosomes, Time Factors, Triazoles, Receptors, N-Methyl-D-Aspartate, Dizocilpine Maleate, Excitatory Amino Acid Antagonists, Glutamic Acid, Excitatory Amino Acid Transporter 2, Receptor, Adenosine A2A, Mice
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