title: Allosteric modulation of related ligand-gated ion channels synergistically induces long-term potentiation in the hippocampus and enhances cognition.
abstract: α5 Subunit-containing GABA(A) receptors (GABA(A)Rs) and α7 neuronal nicotinic-acetylcholine receptors (nAChRs) are members of the Cys-loop family of ligand-gated ion channels (LGICs) that mediate cognitive and attentional processes in the hippocampus. α5 GABA(A)Rs alter network activity by tonic inhibition of CA1/CA3 pyramidal cells of the hippocampus. Postsynaptic α7 nAChRs in the hippocampus regulate inhibitory GABAergic interneuron activity required for synchronization of pyramidal neurons in the CA1, whereas presynaptic 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 1) inhibit α5 GABA(A)Rs and 2) enhance α7 nAChRs causes long-term potentiation (LTP) of mossy fiber stimulation-induced excitatory postsynaptic currents (EPSC) from CA1 pyramidal neurons of rat hippocampal slices. The LTP effect evoked by two compounds is replicated by 3-(2,5-difluorophenyl)-6-(N-ethylindol-5-yl)-1,2,4-triazolo[4,3-b]pyridazine (522-054), a compound we designed to simultaneously inhibit α5 GABA(A)Rs 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 and facilitates attentional states in the five-choice serial reaction time trial with similar receptor antagonist sensitivity. These observations may translate into therapeutic utility of dual action compounds in diseases of hippocampal-based cognitive impairment.
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Irvine, California, USA. tbjohnst@uci.edu
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Johnstone
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Gu
authors.forename: Ryan F
authors.initials: RF
authors.lastname: Yoshimura
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Villegier
authors.forename: Derk J
authors.initials: DJ
authors.lastname: Hogenkamp
authors.forename: Edward R
authors.initials: ER
authors.lastname: Whittemore
authors.forename: Jin-Cheng
authors.initials: JC
authors.lastname: Huang
authors.forename: Minhtam B
authors.initials: MB
authors.lastname: Tran
authors.forename: James D
authors.initials: JD
authors.lastname: Belluzzi
authors.forename: Jerrel L
authors.initials: JL
authors.lastname: Yakel
authors.forename: Kelvin W
authors.initials: KW
authors.lastname: Gee
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D058446:Ligand-Gated Ion Channels / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology; D011978:Receptors, Nicotinic / Q000502:physiology; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579165:Chrna7 protein, rat; C511535:Gabra5 protein, rat; D007211:Indoles; D058446:Ligand-Gated Ion Channels; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor