김선휘 (University of Tennessee Health Science Center)

한빛사논문

조회507

University of Tennessee Health Science Center

Cell Reports, Volume 39, Issue 10, 7 June 2022, 110906 | https://doi.org/10.1016/j.celrep.2022.110906 Neural circuit pathology driven by Shank3 mutation disrupts social behaviors

Sunwhi Kim,1,2 Yong-Eun Kim,1,2 Inuk Song,3 Yusuke Ujihara,1,2 Namsoo Kim,4 Yong-Hui Jiang,5 Henry H. Yin,6 Tae-Ho Lee,3 and Il Hwan Kim1,2,7,*

1Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
2Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA
3Department of Psychology, Virginia Tech, Blacksburg, VA 24061, USA
4Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
5Department of Genetics, Pediatrics and Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA
6Department of Psychology and Neuroscience, Duke University, Durham, NC 27708, USA
7Lead contact

*Correspondence

Abstract

Dysfunctional sociability is a core symptom in autism spectrum disorder (ASD) that may arise from neural-network dysconnectivity between multiple brain regions. However, pathogenic neural-network mechanisms underlying social dysfunction are largely unknown. Here, we demonstrate that circuit-selective mutation (ctMUT) of ASD-risk Shank3 gene within a unidirectional projection from the prefrontal cortex to the basolateral amygdala alters spine morphology and excitatory-inhibitory balance of the circuit. Shank3 ctMUT mice show reduced sociability as well as elevated neural activity and its amplitude variability, which is consistent with the neuroimaging results from human ASD patients. Moreover, the circuit hyper-activity disrupts the temporal correlation of socially tuned neurons to the events of social interactions. Finally, optogenetic circuit activation in wild-type mice partially recapitulates the reduced sociability of Shank3 ctMUT mice, while circuit inhibition in Shank3 ctMUT mice partially rescues social behavior. Collectively, these results highlight a circuit-level pathogenic mechanism of Shank3 mutation that drives social dysfunction.

논문정보

형식Research article
게재일2022년 06월 (BRIC 등록일 2022-10-24)
연구진국외 연구진
분야 생명과학 > 신경생물학

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