최순욱 (Broad Institute of MIT and Harvard) | 한빛사논문 > 한빛사

한빛사논문

조회186

Broad Institute of MIT and Harvard

Cell Rep. Med., April 25, 2024 | https://doi.org/10.1016/j.xcrm.2024.101534 Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice

Baolin Guo,^1,2,7 Tiaotiao Liu,^4,7 Soonwook Choi,^2,3,7Honghui Mao,^1,7 Wenting Wang,¹ Kaiwen Xi,¹ Carter Jones,² Nolan D. Hartley,^2,3 Dayun Feng,¹ Qian Chen,³ Yingying Liu,¹ Ralf D. Wimmer,³ Yuqiao Xie,¹Ningxia Zhao,⁵ Jianjun Ou,⁶ Mario A. Arias-Garcia,² Diya Malhotra,² Yang Liu,¹Sihak Lee,² Sammuel Pasqualoni,² Ryan J. Kast,^2,3 Morgan Fleishman,² Michael M. Halassa,³ Shengxi Wu,^1,* and Zhanyan Fu ^2,3,8,*

¹Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China
²Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
³McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA
⁴School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, China
⁵Xi’an TCM Hospital of Encephalopathy, Shaanxi University of Chinese Medicine, Xi’an 710032, China
⁶Department of Psychiatry, The Second Xiangya Hospital of Central South University, National Clinical Research Center for Mental Disorders, Changsha 410011, China
⁷These authors contributed equally
⁸Lead contact

^*Corresponding authors: correspondence to Shengxi Wu or Zhanyan Fu

Abstract

Thalamocortical (TC) circuits are essential for sensory information processing. Clinical and preclinical studies of autism spectrum disorders (ASDs) have highlighted abnormal thalamic development and TC circuit dysfunction. However, mechanistic understanding of how TC dysfunction contributes to behavioral abnormalities in ASDs is limited. Here, our study on a Shank3 mouse model of ASD reveals TC neuron hyperexcitability with excessive burst firing and a temporal mismatch relationship with slow cortical rhythms during sleep. These TC electrophysiological alterations and the consequent sensory hypersensitivity and sleep fragmentation in Shank3 mutant mice are causally linked to HCN2 channelopathy. Restoring HCN2 function early in postnatal development via a viral approach or lamotrigine (LTG) ameliorates sensory and sleep problems. A retrospective case series also supports beneficial effects of LTG treatment on sensory behavior in ASD patients. Our study identifies a clinically relevant circuit mechanism and proposes a targeted molecular intervention for ASD-related behavioral impairments.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-05-02)
연구진국외 연구진
분야

댓글 작성 로그인

CV 열람하기

연락처 보기