PMID- 32937141 OWN - NLM STAT- MEDLINE DCOM- 20210504 LR - 20210504 IS - 2211-1247 (Electronic) VI - 32 IP - 11 DP - 2020 Sep 15 TI - Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities. PG - 108126 LID - S2211-1247(20)31115-3 [pii] LID - 10.1016/j.celrep.2020.108126 [doi] AB - SETD1A encodes a histone methyltransferase whose de novo mutations are identified in schizophrenia (SCZ) patients and confer a large increase in disease risk. Here, we generate Setd1a mutant mice carrying the frameshift mutation that closely mimics a loss-of-function variant of SCZ. Our Setd1a (+/-) mice display various behavioral abnormalities relevant to features of SCZ, impaired excitatory synaptic transmission in layer 2/3 (L2/3) pyramidal neurons of the medial prefrontal cortex (mPFC), and altered expression of diverse genes related to neurodevelopmental disorders and synaptic functions in the mPFC. RNAi-mediated Setd1a knockdown (KD) specifically in L2/3 pyramidal neurons of the mPFC only recapitulates impaired sociality among multiple behavioral abnormalities of Setd1a (+/-) mice. Optogenetics-assisted selective stimulation of presynaptic neurons combined with Setd1a KD reveals that Setd1a at postsynaptic site is essential for excitatory synaptic transmission. Our findings suggest that reduced SETD1A may attenuate excitatory synaptic function and contribute to the pathophysiology of SCZ. CI - Copyright (c) 2020 The Author(s). Published by Elsevier Inc. All rights reserved. FAU - Nagahama, Kenichiro AU - Nagahama K AD - Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; International Research Center for Neurointelligence (WPI-IRCN), The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo 113-0033, Japan. FAU - Sakoori, Kazuto AU - Sakoori K AD - Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. FAU - Watanabe, Takaki AU - Watanabe T AD - Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; International Research Center for Neurointelligence (WPI-IRCN), The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo 113-0033, Japan. FAU - Kishi, Yusuke AU - Kishi Y AD - Laboratory of Molecular Biology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. FAU - Kawaji, Keita AU - Kawaji K AD - Laboratory of Molecular Biology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. FAU - Koebis, Michinori AU - Koebis M AD - Laboratory of Animal Resources, Center for Disease Biology and Integrated Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. FAU - Nakao, Kazuki AU - Nakao K AD - Laboratory of Animal Resources, Center for Disease Biology and Integrated Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. FAU - Gotoh, Yukiko AU - Gotoh Y AD - International Research Center for Neurointelligence (WPI-IRCN), The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo 113-0033, Japan; Laboratory of Molecular Biology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. FAU - Aiba, Atsu AU - Aiba A AD - Laboratory of Animal Resources, Center for Disease Biology and Integrated Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. FAU - Uesaka, Naofumi AU - Uesaka N AD - Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; International Research Center for Neurointelligence (WPI-IRCN), The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo 113-0033, Japan; Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan. Electronic address: uesaka.cnb@tmd.ac.jp. FAU - Kano, Masanobu AU - Kano M AD - Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; International Research Center for Neurointelligence (WPI-IRCN), The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: mkano-tky@m.u-tokyo.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 3KX376GY7L (Glutamic Acid) RN - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase) RN - EC 2.1.1.43 (Nsccn1 protein, mouse) SB - IM MH - Amino Acid Sequence MH - Animals MH - Base Sequence MH - *Behavior, Animal MH - CRISPR-Cas Systems/genetics MH - Excitatory Postsynaptic Potentials/physiology MH - Female MH - Gene Deletion MH - Gene Expression Regulation MH - Glutamic Acid/metabolism MH - Histone-Lysine N-Methyltransferase/chemistry/*deficiency/genetics/metabolism MH - Humans MH - Male MH - Mice, Inbred ICR MH - Mutation/genetics MH - Neurodevelopmental Disorders/genetics MH - Prefrontal Cortex/metabolism MH - Presynaptic Terminals/physiology MH - Pyramidal Cells/metabolism MH - Schizophrenia/genetics/*physiopathology MH - Social Behavior MH - Synapses/*physiology OTO - NOTNLM OT - H3K4 methylation OT - de novo mutation OT - epigenomics OT - excitatory synapse OT - histone modification OT - layer 2/3 OT - medial prefrontal cortex OT - pyramidal neuron OT - schizophrenia OT - social behavior COIS- Declaration of Interests The authors declare no competing interests. EDAT- 2020/09/17 06:00 MHDA- 2021/05/05 06:00 CRDT- 2020/09/16 20:07 PHST- 2020/01/22 00:00 [received] PHST- 2020/06/17 00:00 [revised] PHST- 2020/08/19 00:00 [accepted] PHST- 2020/09/16 20:07 [entrez] PHST- 2020/09/17 06:00 [pubmed] PHST- 2021/05/05 06:00 [medline] AID - S2211-1247(20)31115-3 [pii] AID - 10.1016/j.celrep.2020.108126 [doi] PST - ppublish SO - Cell Rep. 2020 Sep 15;32(11):108126. doi: 10.1016/j.celrep.2020.108126.