title: The atypical antipsychotic olanzapine disturbs depotentiation by modulating mAChRs and impairs reversal learning.
abstract: Antipsychotic medication is an essential component for treating schizophrenia, which is a serious mental disorder that affects approximately 1% of the global population. Olanzapine (Olz), one of the most frequently prescribed atypical antipsychotics, is generally considered a first-line drug for treating schizophrenia. In contrast to psychotic symptoms, the effects of Olz on cognitive symptoms of schizophrenia are still unclear. In addition, the mechanisms by which Olz affects the neural circuits associated with cognitive function are unknown. Here we show that Olz interrupts depotentiation (reversal of long-term potentiation) without disturbing de novo LTP (long-term potentiation) and LTD (long-term depression). At hippocampal SC-CA1 synapses, inhibition of NMDARs (N-methyl-d-aspartate receptors), mGluRs (metabotropic glutamate receptors), or mAChRs (muscarinic acetylcholine receptors) disrupted depotentiation. In addition, co-activation of NMDARs, mGluRs, and mAChRs reversed stably expressed LTP. Olz inhibits the activation of mAChRs, which amplifies glutamate signaling through enhanced NMDAR opening and Gq (Gq class of G protein)-mediated signal transduction. Behaviorally, Olz impairs spatial reversal learning of mice in the Morris water maze test. Our results uncover a novel mechanism underpinning the cognitive modulation of Olz and show that the anticholinergic property of Olz affects glutamate signaling and synaptic plasticity.
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
authors.forename: Woo Seok
authors.initials: WS
authors.lastname: Song
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Cha
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Yoon
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
authors.forename: Young Seon
authors.initials: YS
authors.lastname: Cho
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
authors.forename: Kyeong-Yeol
authors.initials: KY
authors.lastname: Park
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799, South Korea; Neuroscience Research Institute, Seoul National University Medical Research Center, Seoul, 110-799, South Korea; Seoul National University Bundang Hospital, Seongnam, Gyeonggi, 463-707, South Korea. Electronic address: kmhwany@snu.ac.kr.
authors.forename: Myoung-Hwan
authors.initials: MH
authors.lastname: Kim
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D001569:Benzodiazepines / Q000008:administration & dosage*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D000077152:Olanzapine; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012193:Reversal Learning / Q000187:drug effects*; D012559:Schizophrenia / Q000150:complications / Q000517:prevention & control*; D065852:Spatial Memory / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D018094:Receptors, Metabotropic Glutamate; D011976:Receptors, Muscarinic; D016194:Receptors, N-Methyl-D-Aspartate; D001569:Benzodiazepines; D000077152:Olanzapine
keywords: Antipsychotics; Depotentiation; Olanzapine; Reversal learning; Synaptic plasticity; mAChR