title: Genetic blockade of adenosine A2A receptors induces cognitive impairments and anatomical changes related to psychotic symptoms in mice.
abstract: Schizophrenia is a chronic severe mental disorder with a presumed neurodevelopmental origin, and no effective treatment. Schizophrenia is a multifactorial disease with genetic, environmental and neurochemical etiology. The main theories on the pathophysiology of this disorder include alterations in dopaminergic and glutamatergic neurotransmission in limbic and cortical areas of the brain. Early hypotheses also suggested that nucleoside adenosine is a putative affected neurotransmitter system, and clinical evidence suggests that adenosine adjuvants improve treatment outcomes, especially in poorly responsive patients. Hence, it is important to elucidate the role of the neuromodulator adenosine in the pathophysiology of schizophrenia. A2A adenosine receptor (A2AR) subtypes are expressed in brain areas controlling motivational responses and cognition, including striatum, and in lower levels in hippocampus and cerebral cortex. The aim of this study was to characterize A2AR knockout (KO) mice with complete and specific inactivation of A2AR, as an animal model for schizophrenia. We performed behavioral, anatomical and neurochemical studies to assess psychotic-like symptoms in adult male and female KO and wild-type (WT) littermates. Our results show impairments in inhibitory responses and sensory gating in A2AR KO animals. Hyperlocomotion induced by d-amphetamine and MK-801 was reduced in KO animals when compared to WT littermates. Moreover, A2AR KO animals show motor disturbances, social and cognitive alterations. Finally, behavioral impairments were associated with enlargement of brain lateral ventricles and decreased BDNF levels in the hippocampus. These data highlight the role of adenosine in the pathophysiology of schizophrenia and provide new possibilities for the therapeutic management of schizophrenia.
authors.affiliation: Neurobiology of Behavior Research Group (GReNeC), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Moscoso-Castro
authors.affiliation: Neurobiology of Behavior Research Group (GReNeC), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Gracia-Rubio
authors.affiliation: Unitat de Farmacologia, Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL-Universitat de Barcelona, Barcelona, Spain; Department of Biochemistry and Microbiology, Faculty of Sciences, University of Ghent, Gent, Belgium.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
authors.affiliation: Neurobiology of Behavior Research Group (GReNeC), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain; Neuroscience Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain. Electronic address: olga.valverde@upf.edu.
authors.forename: Olga
authors.initials: O
authors.lastname: Valverde
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000378:metabolism* / Q000473:pathology; D003913:Dextroamphetamine / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005260:Female; D007266:Inhibition, Psychological; D008297:Male; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D011618:Psychotic Disorders / Q000378:metabolism* / Q000473:pathology; D043705:Receptor, Adenosine A2A / Q000172:deficiency* / Q000235:genetics; D012559:Schizophrenia / Q000378:metabolism* / Q000473:pathology; D055139:Sensory Gating / Q000502:physiology; D012919:Social Behavior
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018377:Neurotransmitter Agents; D043705:Receptor, Adenosine A2A; D016291:Dizocilpine Maleate; D003913:Dextroamphetamine
keywords: Adenosine A(2A); BDNF; Cognition; Psychotic behavior; Schizophrenia; Ventricles enlargement