Allosteric modulation of related ligand-gated ion channels synergistically induces long term potentiation in the hippocampus and enhances cognition.

α5 subunit-containing γ-aminobutyric acidA (α5 GABAA) and α7 neuronal nicotinic-acetylcholine receptors (α7 nAChRs) are members of the cys-loop family of ligand-gated ion channels (LGICs) that mediate cognitive and attentional processes in the hippocampus. α5 GABAARs alter network activity by tonic inhibition of CA1/CA3 pyramidal cells of the hippocampus. Post-synaptic α7 nAChRs in the hippocampus regulate inhibitory GABAergic interneuron activity required for synchronization of pyramidal neurons in the CA1, while pre-synaptic α7 nAChRs regulate glutamate release. Can simultaneous allosteric modulation of these LGICs produce synergistic effects on cognition? We show that combined transient application of two allosteric modulators that individually (a) inhibit α5 GABAARs and (b) enhance α7 nAChRs causes long term potentiation (LTP) of mossy fiber stimulation induced excitatory post synaptic currents (EPSC) from CA1 pyramidal neurons of rat hippocampal slices. The LTP effect evoked by two compounds is replicated by 3-(2,5-diflourophenyl)-6-(N-ethylindol-5-yl)-1,2,4-triazolo[4,3-b]pyridazine (522-054), a compound we designed to simultaneously inhibit α5 GABAARs and enhance α7 nAChRs. Selective antagonists for either receptor block sustained EPSC potentiation produced by 522-054. In vivo, 522-054 enhances performance in the radial arm maze (RAM) and facilitates attentional states in the five choice serial reaction time trial (5-CSRTT) with similar receptor antagonist sensitivity. These observations may translate into therapeutic utility of dual action compounds in diseases of hippocampal based cognitive impairment.