Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice.

Autor:	Guo B; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Liu T; School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin 300070, China., Choi S; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA., Mao H; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China., Wang W; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China., Xi K; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China., Jones C; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Hartley ND; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA., Feng D; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China., Chen Q; McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA., Liu Y; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China., Wimmer RD; McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA., Xie Y; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China., Zhao N; Xi'an TCM Hospital of Encephalopathy, Shaanxi University of Chinese Medicine, Xi'an 710032, China., Ou J; Department of Psychiatry, The Second Xiangya Hospital of Central South University, National Clinical Research Center for Mental Disorders, Changsha 410011, China., Arias-Garcia MA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Malhotra D; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Liu Y; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China., Lee S; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Pasqualoni S; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Kast RJ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA., Fleishman M; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Halassa MM; McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA., Wu S; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China. Electronic address: shengxi@fmmu.edu.cn., Fu Z; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA. Electronic address: zfu@broadinstitute.org.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2024 May 21; Vol. 5 (5), pp. 101534. Date of Electronic Publication: 2024 Apr 25.
DOI:	10.1016/j.xcrm.2024.101534
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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