α7-nAChR agonist enhances neural plasticity in the hippocampus via a GABAergic circuit

Agonists of the α₇-nicotinic acetylcholine receptor (α₇-nAChR) have entered clinical trials as procognitive agents for treating schizophrenia and Alzheimer's disease. The most advanced compounds are orthosteric agonists, which occupy the ligand binding site. At the molecular level, agonist activation of α₇-nAChR is reasonably well understood. However, the consequences of activating α₇-nAChRs on neural circuits underlying cognition remain elusive. Here we report that an α₇-nAChR agonist (FRM-17848) enhances long-term potentiation (LTP) in rat septo-hippocampal slices far below the cellular EC₅₀ but at a concentration that coincides with multiple functional outcome measures as we reported in Stoiljkovic M, Leventhal L, Chen A, Chen T, Driscoll R, Flood D, Hodgdon H, Hurst R, Nagy D, Piser T, Tang C, Townsend M, Tu Z, Bertrand D, Koenig G, Hajós M. Biochem Pharmacol 97: 576-589, 2015. In this same concentration range, we observed a significant increase in spontaneous γ-aminobutyric acid (GABA) inhibitory postsynaptic currents and a moderate suppression of excitability in whole cell recordings from rat CA1 pyramidal neurons. This modulation of GABAergic activity is necessary for the LTP-enhancing effects of FRM-17848, since inhibiting GABA_A α₅-subunit-containing receptors fully reversed the effects of the α₇-nAChR agonist. These data suggest that α₇-nAChR agonists may increase synaptic plasticity in hippocampal slices, at least in part, through a circuit-level enhancement of a specific subtype of GABAergic receptor.