Participants enc network

Project 5 – Cycle 4-2013: Role of adenosine A2A receptors in the control of

synaptic plasticity in the prefrontal cortex – relevance for
attention deficit and hyperactivity disorders

Home Institute:
Principle Investigator:
Rodrigo Cunha
Host Institute:
Principle Investigator:
Huib Mansvelder

Executive Summary
Caffeine is the most widely consumed psychoactive drug worldwide; its only known
molecular targets at non-toxic doses are adenosine receptors, namely the
antagonism of adenosine A2A receptors (A2AR) when consumed chronically. Caffeine and A2AR antagonists have been shown to attenuate different neuropsychiatric disorders resulting from abnormal plastic changes of different brain circuits, such as depression, Alzheimer’s disease (affecting limbic circuits) or Parkinson’s disease (affecting striatal circuits). Caffeine has also been therapeutically exploited to control attention deficit and hyperactivity disorders (ADHD) in pilot clinical trial. Accordingly, we recently reported that caffeine prevents attention set shifting deficits characteristic of juvenile spontaneous hypertensive rats (SHR), the best accepted animal model of ADHD; this was accompanied by an increased of A2AR density in the prefrontal cortex (PFC), one of the brain region prominently associated with ADHD. Very little is known about the localization and function of A2AR in the PFC, namely if A2ARs play a key role in controlling synaptic plasticity, as shown in the hippocampus, which is proposed to underlie the ability of caffeine or A2AR antagonists to control memory deficits. However, it is known that A2AR control habit formation and reversal learning, two behavioural responses dependent on PFC circuits. This project brings forward the provocative hypothesis that A2AR in the PFC play a key role in controlling the shift between automatic and exploratory behaviors; additionally, we also post that abnormal A2AR function in the PFC is a main contributor for impulsivity and attention deficits characteristic of ADHD. Therefore, this project merges several inter-twined aims pertinent to the understanding of the physiopathological role of A2AR in the PFC: 1) defining the role of adenosine neuromodulation system in the control of glutamatergic synaptic transmission and plasticity in the PFC; 2) establishing a putative key role of PFC A2AR in the control of behavioral PFC-dependent responses; 3) exploring if ADHD modifies the A2AR-mediated modulation of synaptic plasticity in the PFC; 4) testing if the selective manipulation of PFC A2AR relieves ADHD symptoms, as does caffeine consumption. Carrying out this novel and ambitious project will require merging the expertise of Cunha’s lab in manipulating A2AR and ADHD animal models with the expertise of Mansvelder’s lab in the PFC neurophysiology and behavioural correlates. It is expected that this project will provide a balanced training in basic neurophysiology and in its clinical relevance, while providing the candidate with a truly multi-disciplinary training in state-of-the-art approaches in electrophysiology, genetic manipulations, optogenetic and behavior analysis.


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