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Nat. Commun., Published 27 August 2022 | https://doi.org/10.1038/s41467-022-32748-5 Early postnatal serotonin modulation prevents adult-stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming

Hyosang Kim^1,8, Doyoun Kim^2,8, Yisul Cho^3,8, Kyungdeok Kim², Junyeop Daniel Roh², Yangsik Kim⁴, Esther Yang⁵, Seong Soon Kim⁶, Sunjoo Ahn⁶, Hyun Kim⁵, Hyojin Kang⁷, Yongchul Bae^3* & Eunjoon Kim^1,2*

¹Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon 34141, Korea. ²Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon 34141, Korea. ³Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu 41940, Korea. ⁴Graduate School of Biomedical Engineering, Korea Advanced Institute for Science and Technology (KAIST), Daejeon 34141, Korea. ⁵Department of Anatomy and Division of Brain Korea 21, Biomedical Science, College of Medicine, Korea University, Seoul 02841, Korea. ⁶Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Korea. ⁷Division of National Supercomputing, Korea Institute of Science and Technology Information, Daejeon 34141, Korea. ⁸These authors contributed equally: Hyosang Kim, Doyoun Kim, Yisul Cho.

^*Corresponding author.

Abstract

Autism spectrum disorder is characterized by early postnatal symptoms, although little is known about the mechanistic deviations that produce them and whether correcting them has long-lasting preventive effects on adult-stage deficits. ARID1B, a chromatin remodeler implicated in neurodevelopmental disorders, including autism spectrum disorder, exhibits strong embryonic- and early postnatal-stage expression. We report here that Arid1b-happloinsufficient (Arid1b^+/–) mice display autistic-like behaviors at juvenile and adult stages accompanied by persistent decreases in excitatory synaptic density and transmission. Chronic treatment of Arid1b^+/– mice with fluoxetine, a selective serotonin-reuptake inhibitor, during the first three postnatal weeks prevents synaptic and behavioral deficits in adults. Mechanistically, these rescues accompany transcriptomic changes, including upregulation of FMRP targets and normalization of HDAC4/MEF2A-related transcriptional regulation of the synaptic proteins, SynGAP1 and Arc. These results suggest that chronic modulation of serotonergic receptors during critical early postnatal periods prevents synaptic and behavioral deficits in adult Arid1b^+/– mice through transcriptional reprogramming.

논문정보

형식Research article
게재일2022년 08월 (BRIC 등록일 2022-09-08)
연구진국내 연구진
분야 생명과학 > 생리학

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