Elsevier

Biological Psychiatry

Volume 78, Issue 11, 1 December 2015, Pages 763-774
Biological Psychiatry

Archival Report
Deletion of Adenosine A2A Receptors From Astrocytes Disrupts Glutamate Homeostasis Leading to Psychomotor and Cognitive Impairment: Relevance to Schizophrenia

https://doi.org/10.1016/j.biopsych.2015.02.026Get rights and content

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.

Section snippets

Methods and Materials

For detailed methods see Supplement 1.

Selective A2AR Deletion in Astrocytes Triggers Psychomotor and Cognitive Endophenotypes Resembling Schizophrenia

To demonstrate cell type specificity of A2AR gene deletion in Gfa2-A2AR KO mice, we used flow cytometry to separate astrocytes (GFAP-positive cells) and neurons (β-tubulin III-positive cells) from whole-brain lysates of Cre-positive and -negative Gfa2-A2AR KO mice (32). Polymerase chain reaction analyses demonstrated the successful A2AR gene deletion in GFAP-expressing astrocytes sorted from Gfa2-A2AR KO mice (Cre+) but not in sorted neurons (β-tubulin III-positive cells) from these same mice

Discussion

The present study shows that a mouse transgenic line with a selective deletion of A2AR in astrocytes exhibits motor and memory dysfunctions relevant to schizophrenia, namely the exacerbation of MK-801-induced psychomotor response and a decrease of working memory. This was paralleled by neurochemical alterations in glutamatergic synapses typified by an enhanced astrocytic uptake of glutamate, an enhanced release of glutamate from nerve terminals, an upregulation of NR2B-containing NMDA

Acknowledgements and Disclosures

The work was supported by National Institutes of Health/National Institute of Neurological Disorders and Stroke and National Institute of Mental Health grants NS041083-11, NS073947, and MH083973; National Alliance for Research on Schizophrenia and Depression, Defense Advanced Research Projects Agency grants 09-68-ESR-FP-010 and W911NF-10-1-0059; the Portuguese Foundation for Science and Technology (FCT, PTDC/SAU-NSC/122254/2010) and Quadro de Referência Estratégico Nacional

References (68)

  • J.H. Wang et al.

    Reduced startle habituation and prepulse inhibition in mice lacking the adenosine A2A receptor

    Behav Brain Res

    (2003)
  • J.F. Chen et al.

    Selective attenuation of psychostimulant-induced behavioral responses in mice lacking A2A adenosine receptors

    Neuroscience

    (2000)
  • A. Kurumaji et al.

    An increase in [3H]CGS21680 binding in the striatum of postmortem brains of chronic schizophrenics

    Brain Res

    (1998)
  • M. Milanese et al.

    Glutamate release from astrocytic gliosomes under physiological and pathological conditions

    Int Rev Neurobiol

    (2009)
  • S. Namura et al.

    Inhibition of glial glutamate transporter GLT-I augments brain edema after transient focal cerebral ischemia in mice

    Neurosci Lett

    (2002)
  • P. Singer et al.

    Working memory and the homeostatic control of brain adenosine by adenosine kinase

    Neuroscience

    (2012)
  • K. Blot et al.

    The effect of non-competitive NMDA receptor antagonist MK-801 on neuronal activity in rodent prefrontal cortex: An animal model for cognitive symptoms of schizophrenia

    J Physiol Paris

    (2013)
  • J. Han et al.

    Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD

    Cell

    (2012)
  • M.M. Halassa et al.

    Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss

    Neuron

    (2009)
  • A. Suzuki et al.

    Astrocyte-neuron lactate transport is required for long-term memory formation

    Cell

    (2011)
  • R.A. Cunha

    Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: Different roles, different sources and different receptors

    Neurochem Int

    (2001)
  • A. Sanz-Clemente et al.

    Activated CaMKII couples GluN2B and casein kinase 2 to control synaptic NMDA receptors

    Cell Rep

    (2013)
  • M. Wang et al.

    NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex

    Neuron

    (2013)
  • B. Moghaddam et al.

    From revolution to evolution: The glutamate hypothesis of schizophrenia and its implication for treatment

    Neuropsychopharmacology

    (2012)
  • C.B. Mikell et al.

    The hippocampus and nucleus accumbens as potential therapeutic targets for neurosurgical intervention in schizophrenia

    Stereotact Funct Neurosurg

    (2009)
  • C.M. Anderson et al.

    Astrocyte glutamate transport: review of properties, regulation, and physiological functions

    Glia

    (2000)
  • M.M. Halassa et al.

    Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior

    Annu Rev Physiol

    (2010)
  • R.E. Smith et al.

    Expression of excitatory amino acid transporter transcripts in the thalamus of subjects with schizophrenia

    Am J Psychiatry

    (2001)
  • C. Matute et al.

    Increased expression of the astrocytic glutamate transporter GLT-I in the prefrontal cortex of schizophrenics

    Glia

    (2005)
  • J.F. Deakin et al.

    Frontal cortical and left temporal glutamatergic dysfunction in schizophrenia

    J Neurochem

    (1989)
  • J.S. Schneider et al.

    Chronic neuroleptic treatment alters expression of glial glutamate transporter GLT-1 mRNA in the striatum

    Neuroreport

    (1998)
  • M. Melone et al.

    The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine

    Mol Psychiatry

    (2001)
  • L. Bragina et al.

    GLT-1 down-regulation induced by clozapine in rat frontal cortex is associated with synaptophysin up-regulation

    J Neurochem

    (2006)
  • A. Vallejo-Illarramendi et al.

    Clozapine reduces GLT-1 expression and glutamate uptake in astrocyte cultures

    Glia

    (2005)
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