Deletion of Adenosine A2A Receptors From Astrocytes Disrupts Glutamate Homeostasis Leading to Psychomotor and Cognitive Impairment: Relevance to Schizophrenia
Biological Psychiatry. 2015-12-01; 78(11): 763-774
DOI: 10.1016/j.biopsych.2015.02.026
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Matos M(1), Shen HY(2), Augusto E(1), Wang Y(3), Wei CJ(3), Wang YT(4),
Agostinho P(5), Boison D(2), Cunha RA(5), Chen JF(6).
Author information:
(1)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.
(2)R.S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland,
Oregon.
(3)Department of Neurology, Boston University School of Medicine, Boston,
Massachusetts.
(4)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.
(5)Center for Neuroscience and Cell Biology, University of Coimbra, Portugal;
Faculty of Medicine, University of Coimbra, Portugal.
(6)Department of Neurology, Boston University School of Medicine, Boston,
Massachusetts. Electronic address: .
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.
Copyright © 2015. Published by Elsevier Inc.