천성근 (St. Jude Children’s Research Hospital, 현 전북대학교 의학전문대학원) | 한빛사논문 > 한빛사

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St. Jude Children’s Research Hospital, 현 전북대학교 의학전문대학원

Nat. Med., Published online 28 November 2016 | doi:10.1038/nm.4240 Thalamic miR-338-3p mediates auditory thalamocortical disruption and its late onset in models of 22q11.2 microdeletion

Abstract

Sungkun Chun^1,3,4, Fei Du^1,3,4, Joby J Westmoreland^1,3,4, Seung Baek Han¹, Yong-Dong Wang², Donnie Eddins¹, Ildar T Bayazitov¹, Prakash Devaraju¹, Jing Yu¹, Marcia M Mellado Lagarde¹, Kara Anderson¹ & Stanislav S Zakharenko¹¹Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA. ²Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA. ³Present addresses: Department of Physiology, Chonbuk National University Medical School, South Korea (S.C.); Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA (F.D.); Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA (J.J.W.). ⁴These authors contributed equally to this work.

Correspondence to : Stanislav S Zakharenko

Abstract
Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. Here we show that these auditory TC phenotypes have a delayed onset in 22q11DS mice and are associated with an age-dependent reduction of miR-338-3p, a miRNA that targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the TC abnormalities, and deletion of Mir338 (which encodes miR-338-3p) or reduction of miR-338-3p expression mimicked the TC and behavioral deficits and eliminated the age dependence of these deficits. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory TC signaling in 22q11DS mice, and it may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset.

논문정보

형식Research article
게재일2016년 11월 (BRIC 등록일 2016-12-08)
연구진국외 연구진
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