The study of psychiatric disorders usually focuses on emotional symptoms assessment. However, cognitive deficiencies frequently constitute the core symptoms, are often poorly controlled and handicap individual's quality of life. Adenosine receptors, through the control of both dopamine and glutamate systems, have been implicated in the pathophysiology of several psychiatric disorders such as schizophrenia and attention deficit/hyperactivity disorder. Indeed, clinical data indicate that poorly responsive schizophrenia patients treated with adenosine adjuvants show improved treatment outcomes. The A2A adenosine receptor subtype (A2AR) is highly expressed in brain areas controlling cognition and motivational responses including the striatum, hippocampus and cerebral cortex. Accordingly, we study the role of A2AR in the regulation of cognitive processes based on a complete cognitive behavioural analysis coupled with the assessment of neurogenesis and sub-synaptic protein expression in adult and middle-aged A2AR constitutional knockout mice and wild-type littermates. Our results show overall cognitive impairments in A2AR knockout mice associated with a decrease in new-born hippocampal neuron proliferation and concomitant changes in synaptic protein expression, in both the prefrontal cortex and the hippocampus. These results suggest a deficient adenosine signalling in cognitive processes, thus providing new opportunities for the therapeutic management of cognitive deficits associated with psychiatric disorders.

This study was supported by MINECO (SAF 2013-41761-RFEDER, SAF 2014-55700-P, SAF 2016-75966-R, FEDER, PCIN-2013-019-C03-03), Ministry of Health (ReticeISCIIIeRD/12/0028/0024-FEDER; RD16/017/010-FEDER, PIE14/00034), Plan Nacional sobre Drogas (2014/020), IWT (SBO-140028), Fundacio la Marato de TV3 (Grant 20152031), UE Medbioinformatic project (grant number 634143) and Generalitat de Catalunya (2014 SGR 34, 2014 SGR 1251). IG-R was funded by an FPI fellowship, BES-2011-046655, associated with SAF 2010-15793.