Archival ReportDeletion of Adenosine A2A Receptors From Astrocytes Disrupts Glutamate Homeostasis Leading to Psychomotor and Cognitive Impairment: Relevance 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)
- et al.
Neurobiology of schizophrenia
Neuron
(2006) - et al.
Targeting glutamate synapses in schizophrenia
Trends Mol Med
(2011) Working memory and long-term memory deficits in schizophrenia: Is there a common substrate?
Psychiatry Res
(2009)- et al.
NMDA receptors and schizophrenia
Curr Opin Pharmacol
(2007) - et al.
Roles of glial cells in schizophrenia: Possible targets for therapeutic approaches
Neurobiol Dis
(2013) - et al.
Comparison of glutamate and gamma-aminobutyric acid uptake binding sites in frontal and temporal lobes in schizophrenia
Biol Psychiatry
(1998) - et al.
Adenosine and brain function
Int Rev Neurobiol
(2005) - et al.
Adenosine hypothesis of schizophrenia—Opportunities for pharmacotherapy
Neuropharmacology
(2012) - et al.
The adenosine neuromodulation system in schizophrenia
Int Rev Neurobiol
(2014) - et al.
Adenosine A2A agonists: A potential new type of atypical antipsychotic
Neuropsychopharmacology
(1997)
Reduced startle habituation and prepulse inhibition in mice lacking the adenosine A2A receptor
Behav Brain Res
Selective attenuation of psychostimulant-induced behavioral responses in mice lacking A2A adenosine receptors
Neuroscience
An increase in [3H]CGS21680 binding in the striatum of postmortem brains of chronic schizophrenics
Brain Res
Glutamate release from astrocytic gliosomes under physiological and pathological conditions
Int Rev Neurobiol
Inhibition of glial glutamate transporter GLT-I augments brain edema after transient focal cerebral ischemia in mice
Neurosci Lett
Working memory and the homeostatic control of brain adenosine by adenosine kinase
Neuroscience
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
Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD
Cell
Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss
Neuron
Astrocyte-neuron lactate transport is required for long-term memory formation
Cell
Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: Different roles, different sources and different receptors
Neurochem Int
Activated CaMKII couples GluN2B and casein kinase 2 to control synaptic NMDA receptors
Cell Rep
NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex
Neuron
From revolution to evolution: The glutamate hypothesis of schizophrenia and its implication for treatment
Neuropsychopharmacology
The hippocampus and nucleus accumbens as potential therapeutic targets for neurosurgical intervention in schizophrenia
Stereotact Funct Neurosurg
Astrocyte glutamate transport: review of properties, regulation, and physiological functions
Glia
Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior
Annu Rev Physiol
Expression of excitatory amino acid transporter transcripts in the thalamus of subjects with schizophrenia
Am J Psychiatry
Increased expression of the astrocytic glutamate transporter GLT-I in the prefrontal cortex of schizophrenics
Glia
Frontal cortical and left temporal glutamatergic dysfunction in schizophrenia
J Neurochem
Chronic neuroleptic treatment alters expression of glial glutamate transporter GLT-1 mRNA in the striatum
Neuroreport
The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine
Mol Psychiatry
GLT-1 down-regulation induced by clozapine in rat frontal cortex is associated with synaptophysin up-regulation
J Neurochem
Clozapine reduces GLT-1 expression and glutamate uptake in astrocyte cultures
Glia
Cited by (123)
Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain
2024, Brain, Behavior, and ImmunityPostweaning intermittent sleep deprivation enhances defensive attack in adult female mice via the microbiota-gut-brain axis
2024, Progress in Neuro-Psychopharmacology and Biological PsychiatryPurinergic receptors in cognitive disturbances
2023, Neurobiology of Disease