title: Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: relevance to schizophrenia.
abstract: 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.
authors: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts; Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal.
authors: Marco
authors: M
authors: Matos
authors: R.S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon.
authors: Hai-Ying
authors: HY
authors: Shen
authors: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts; Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal.
authors: Elisabete
authors: E
authors: Augusto
authors: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts.
authors: Yumei
authors: Y
authors: Wang
authors: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts.
authors: Catherine J
authors: CJ
authors: Wei
authors: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts; Department of Medicine and Brain Research Centre, Vancouver Hospital and Health Sciences Centre, University of British Columbia, Vancouver, Canada.
authors: Yu Tian
authors: YT
authors: Wang
authors: Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal.
authors: Paula
authors: P
authors: Agostinho
authors: R.S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon.
authors: Detlev
authors: D
authors: Boison
authors: Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal.
authors: Rodrigo A
authors: RA
authors: Cunha
authors: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts. Electronic address: chenjf@bu.edu.
authors: Jiang-Fan
authors: JF
authors: Chen
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics*; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011596:Psychomotor Disorders / Q000235:genetics / Q000473:pathology*; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000172:deficiency* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D018691:Excitatory Amino Acid Antagonists; D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D016194:Receptors, N-Methyl-D-Aspartate; D014230:Triazoles; D018698:Glutamic Acid; C020889:dihydrokainic acid; D016291:Dizocilpine Maleate; D007608:Kainic Acid
keywords: A(2A)R; Adenosine; Astrocytes; GLT-I; NMDA-R; Schizophrenia