title: α7-nAChR agonist enhances neural plasticity in the hippocampus via a GABAergic circuit.
abstract: 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 EC50but 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 GABAAα5-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.
authors.affiliation: FORUM Pharmaceuticals, Inc., Waltham, Massachusetts; and matt.townsend@abbvie.com.
authors.forename: Matthew
authors.initials: M
authors.lastname: Townsend
authors.affiliation: Cerebrasol, Ltd., Montreal, Quebec City, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Whyment
authors.affiliation: Cerebrasol, Ltd., Montreal, Quebec City, Canada.
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Walczak
authors.affiliation: Cerebrasol, Ltd., Montreal, Quebec City, Canada.
authors.forename: Ross
authors.initials: R
authors.lastname: Jeggo
authors.affiliation: Cerebrasol, Ltd., Montreal, Quebec City, Canada.
authors.forename: Marco
authors.initials: M
authors.lastname: van den Top
authors.affiliation: FORUM Pharmaceuticals, Inc., Waltham, Massachusetts; and.
authors.forename: Dorothy G
authors.initials: DG
authors.lastname: Flood
authors.affiliation: FORUM Pharmaceuticals, Inc., Waltham, Massachusetts; and.
authors.forename: Liza
authors.initials: L
authors.lastname: Leventhal
authors.affiliation: FORUM Pharmaceuticals, Inc., Waltham, Massachusetts; and.
authors.forename: Holger
authors.initials: H
authors.lastname: Patzke
authors.affiliation: FORUM Pharmaceuticals, Inc., Waltham, Massachusetts; and.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Koenig
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D000077265:Donepezil; D005071:Evoked Potentials / Q000187:drug effects / Q000235:genetics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018682:GABA Agents / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D007189:Indans / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects*; D008297:Male; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009865:Oocytes; D010880:Piperidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000494:pharmacology; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: C000604696:7-fluoro-N-quinuclidin-3-yl)benzo(b)thiophene-2-carboxamide; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018682:GABA Agents; D007189:Indans; D018722:Nicotinic Agonists; D010880:Piperidines; D011812:Quinuclidines; D013876:Thiophenes; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000077265:Donepezil
keywords: Alzheimer's disease; FRM-17848; GABAA α5-receptor; schizophrenia; α7-nAChR