GABAB receptor modulation - to B or not to be B a pro-cognitive medicine?

Metabotropic GABAB receptors clearly modify cognitive performance in preclinical animal models, yet translation to treating human disease has been elusive. Compared to their ionotropic GABAA receptor counterpart GABAB receptors not only regulate postsynaptic excitability but also regulate diverse synaptic inputs by presynaptically inhibiting neurotransmitter release. As such, the choice of agonist, antagonist, −ve or +ve modulator as well as CNS exposure level, timing of delivery and longevity of action strongly influence the probability of unlocking the procognitive potential of GABAB receptors in human disease. Quantitative clinical analysis of target/mechanistic engagement of GABAB receptors within cognitive circuits at the level of distinct pre-synaptic and post-synaptic subpopulations is required to determine the optimal pharmacological/dosing profile for different cognitive disorders.