title: Potentiation of Acetylcholine-Mediated Facilitation of Inhibitory Synaptic Transmission by an Azaindolizione Derivative, ZSET1446 (ST101), in the Rat Hippocampus.
abstract: The integrity of the hippocampal network depends on the coordination of excitatory and inhibitory signaling, which are under dynamic control by various regulatory influences such as the cholinergic systems. ZSET1446 (ST101; spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) is a newly synthesized azaindolizinone derivative that significantly improves learning deficits in various types of Alzheimer disease (AD) models in rats. We examined the effect of ZSET1446 on the nicotinic acetylcholine (ACh) receptor (nAChR)-mediated regulation of synaptic transmission in hippocampal slices of rats. ZSET1446 significantly potentiated the facilitatory effect of nicotine and ACh on the frequency of spontaneous postsynaptic currents (sPSCs) recorded in CA1 pyramidal neurons with a maximum effect at 100 pM (tested range, 10 pM-1000 pM). The basal sPSC frequency without ACh was not affected. Such potentiation by ZSET1446 was observed in both the pharmacologic isolations of inhibitory and excitatory sPSCs and markedly reduced by blockade of either α7 or α4β2 nAChRs. ZSET1446 did not affect ACh-activated inward currents or depolarization of interneurons in the stratum radiatum and the lacunosum moleculare. These results indicate that ZSET1446 potentiates the nicotine-mediated enhancement of synaptic transmission in the hippocampal neurons without affecting nAChRs themselves, providing a novel possible mechanism of procognitive action that might improve learning deficits in clinical therapy.
authors.affiliation: Central Research Laboratory, Zenyaku Kogyo Co., Ltd. (K.T., Y.Y., M.H.,) and Department of Neuroscience, Jikei University School of Medicine, Tokyo Japan (F.K.) Kentaro_Takeda@mail.zenyaku.co.jp.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Central Research Laboratory, Zenyaku Kogyo Co., Ltd. (K.T., Y.Y., M.H.,) and Department of Neuroscience, Jikei University School of Medicine, Tokyo Japan (F.K.).
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Central Research Laboratory, Zenyaku Kogyo Co., Ltd. (K.T., Y.Y., M.H.,) and Department of Neuroscience, Jikei University School of Medicine, Tokyo Japan (F.K.).
authors.forename: Masataka
authors.initials: M
authors.lastname: Hino
authors.affiliation: Central Research Laboratory, Zenyaku Kogyo Co., Ltd. (K.T., Y.Y., M.H.,) and Department of Neuroscience, Jikei University School of Medicine, Tokyo Japan (F.K.).
authors.forename: Fusao
authors.initials: F
authors.lastname: Kato
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D007189:Indans / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: D007189:Indans; D013141:Spiro Compounds; C511224:spiro(imidazo-(1,2-a)pyridine-3,2-indan)-2(3H)-one; D000109:Acetylcholine