A fragile balance: perturbation of GABA mediated circuit in prefrontal cortex generates high intraindividual performance variability.

Abstract

High intraindividual performance variability is one of the most robust findings to emerge in cognitive-experimental research of attention deficit hyperactivity disorder (ADHD). Evidences from studies incorporating structural or functional human brain mapping methods indicate that this increased intraindividual variability is not simply a sequel of general brain dysfunction, but is likely related to the functioning of neural circuits that engage the prefrontal cortex, particularly the dorsolateral areas (dlPFC). In order to examine further the anatomical and pharmacological substrate responsible for this high intraindividual variability disorder, we injected GABA(A) antagonist (bicuculline) or GABA(A) agonist (muscimol) in the dlPFC of monkeys performing a reflexive oculomotor task. Here we show that, whereas GABA(A) agonist injection induced no or minimal impairments, injection of GABA(A) antagonist dramatically increased the intraindividual variability of saccade response time and of saccade spatial accuracy (amplitude and direction). Overall, this study demonstrates that the balance between excitatory/inhibitory activities in the dlPFC is fragile but crucial, since local micro-injection of GABA(A) antagonist can induce marked behavioural effects. It also reveals that higher cognitive areas such as the dlPFC are markedly capable to influence the productions and metrics of reflexive movements. Altogether, this study provides promising perspectives for the development of new therapeutic strategies for the treatment of diseases in which high intravariability disorders are a prominent feature.