Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects

Yang Zhou; Tobias Kaiser; Patrícia Monteiro; Xiangyu Zhang; Marie S. Van der Goes; Dongqing Wang; Boaz Barak; Menglong Zeng; Chenchen Li; Congyi Lu; Michael Wells; Aldo Amaya; Shannon Nguyen; Michael Lewis; Neville Sanjana; Yongdi Zhou; Mingjie Zhang; Feng Zhang; Zhanyan Fu; Guoping Feng

doi:10.1016/j.neuron.2015.11.023

Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects

Yang Zhou, Tobias Kaiser, Patrícia Monteiro, Xiangyu Zhang, Marie S. Van der Goes, Dongqing Wang, Boaz Barak, Menglong Zeng, Chenchen Li, Congyi Lu, Michael Wells, Aldo Amaya, Shannon Nguyen, Michael Lewis, Neville Sanjana, Yongdi Zhou, Mingjie Zhang, Feng Zhang, Zhanyan Fu, Guoping Feng^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

233 Scopus citations

Abstract

Genetic studies have revealed significant overlaps of risk genes among psychiatric disorders. However, it is not clear how different mutations of the same gene contribute to different disorders. We characterized two lines of mutant mice with Shank3 mutations linked to ASD and schizophrenia. We found both shared and distinct synaptic and behavioral phenotypes. Mice with the ASD-linked InsG3680 mutation manifest striatal synaptic transmission defects before weaning age and impaired juvenile social interaction, coinciding with the early onset of ASD symptoms. On the other hand, adult mice carrying the schizophrenia-linked R1117X mutation show profound synaptic defects in prefrontal cortex and social dominance behavior. Furthermore, we found differential Shank3 mRNA stability and SHANK1/2 upregulation in these two lines. These data demonstrate that different alleles of the same gene may have distinct phenotypes at molecular, synaptic, and circuit levels in mice, which may inform exploration of these relationships in human patients.

Original language	English
Pages (from-to)	147-162
Number of pages	16
Journal	Neuron
Volume	89
Issue number	1
DOIs	https://doi.org/10.1016/j.neuron.2015.11.023
State	Published - 6 Jan 2016
Externally published	Yes

Funding

Funders	Funder number
Broad Institute of MIT
Harvard
Merkin
Poitras Center for Affective Disorders Research
Research Grant Council of Hong Kong	AoE/M09/12
Searle Scholars , Klingenstein , Vallee
Shenzhen Overseas Innovation Team Project	KQTD20140630180249366
Simons Center for the Social Brain
Simons Foundations
National Science Foundation
National Institutes of Health	DP1-MH100706
National Institutes of Health
National Institute of Mental Health	R01MH097104
National Institute of Mental Health
National Institute of Neurological Disorders and Stroke	R01-NS 07312401
National Institute of Neurological Disorders and Stroke
Brain and Behavior Research Foundation
Damon Runyon Cancer Research Foundation
Massachusetts Institute of Technology
Nancy Lurie Marks Family Foundation
Autism Science Foundation
National Alliance for Research on Schizophrenia and Depression
Stanley Center for Psychiatric Research, Broad Institute
Simons Foundation Autism Research Initiative
Fundação para a Ciência e a Tecnologia	SFRH/BD/33894/2009
Fundação para a Ciência e a Tecnologia

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10.1016/j.neuron.2015.11.023

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Zhou, Y., Kaiser, T., Monteiro, P., Zhang, X., Van der Goes, M. S., Wang, D., Barak, B., Zeng, M., Li, C., Lu, C., Wells, M., Amaya, A., Nguyen, S., Lewis, M., Sanjana, N., Zhou, Y., Zhang, M., Zhang, F., Fu, Z., & Feng, G. (2016). Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects. Neuron, 89(1), 147-162. https://doi.org/10.1016/j.neuron.2015.11.023

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title = "Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects",

abstract = "Genetic studies have revealed significant overlaps of risk genes among psychiatric disorders. However, it is not clear how different mutations of the same gene contribute to different disorders. We characterized two lines of mutant mice with Shank3 mutations linked to ASD and schizophrenia. We found both shared and distinct synaptic and behavioral phenotypes. Mice with the ASD-linked InsG3680 mutation manifest striatal synaptic transmission defects before weaning age and impaired juvenile social interaction, coinciding with the early onset of ASD symptoms. On the other hand, adult mice carrying the schizophrenia-linked R1117X mutation show profound synaptic defects in prefrontal cortex and social dominance behavior. Furthermore, we found differential Shank3 mRNA stability and SHANK1/2 upregulation in these two lines. These data demonstrate that different alleles of the same gene may have distinct phenotypes at molecular, synaptic, and circuit levels in mice, which may inform exploration of these relationships in human patients.",

author = "Yang Zhou and Tobias Kaiser and Patr{\'i}cia Monteiro and Xiangyu Zhang and {Van der Goes}, {Marie S.} and Dongqing Wang and Boaz Barak and Menglong Zeng and Chenchen Li and Congyi Lu and Michael Wells and Aldo Amaya and Shannon Nguyen and Michael Lewis and Neville Sanjana and Yongdi Zhou and Mingjie Zhang and Feng Zhang and Zhanyan Fu and Guoping Feng",

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Zhou, Y, Kaiser, T, Monteiro, P, Zhang, X, Van der Goes, MS, Wang, D, Barak, B, Zeng, M, Li, C, Lu, C, Wells, M, Amaya, A, Nguyen, S, Lewis, M, Sanjana, N, Zhou, Y, Zhang, M, Zhang, F, Fu, Z & Feng, G 2016, 'Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects', Neuron, vol. 89, no. 1, pp. 147-162. https://doi.org/10.1016/j.neuron.2015.11.023

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T1 - Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects

AU - Zhou, Yang

AU - Kaiser, Tobias

AU - Monteiro, Patrícia

AU - Zhang, Xiangyu

AU - Van der Goes, Marie S.

AU - Wang, Dongqing

AU - Barak, Boaz

AU - Zeng, Menglong

AU - Li, Chenchen

AU - Lu, Congyi

AU - Wells, Michael

AU - Amaya, Aldo

AU - Nguyen, Shannon

AU - Lewis, Michael

AU - Sanjana, Neville

AU - Zhou, Yongdi

AU - Zhang, Mingjie

AU - Zhang, Feng

AU - Fu, Zhanyan

AU - Feng, Guoping

PY - 2016/1/6

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N2 - Genetic studies have revealed significant overlaps of risk genes among psychiatric disorders. However, it is not clear how different mutations of the same gene contribute to different disorders. We characterized two lines of mutant mice with Shank3 mutations linked to ASD and schizophrenia. We found both shared and distinct synaptic and behavioral phenotypes. Mice with the ASD-linked InsG3680 mutation manifest striatal synaptic transmission defects before weaning age and impaired juvenile social interaction, coinciding with the early onset of ASD symptoms. On the other hand, adult mice carrying the schizophrenia-linked R1117X mutation show profound synaptic defects in prefrontal cortex and social dominance behavior. Furthermore, we found differential Shank3 mRNA stability and SHANK1/2 upregulation in these two lines. These data demonstrate that different alleles of the same gene may have distinct phenotypes at molecular, synaptic, and circuit levels in mice, which may inform exploration of these relationships in human patients.

AB - Genetic studies have revealed significant overlaps of risk genes among psychiatric disorders. However, it is not clear how different mutations of the same gene contribute to different disorders. We characterized two lines of mutant mice with Shank3 mutations linked to ASD and schizophrenia. We found both shared and distinct synaptic and behavioral phenotypes. Mice with the ASD-linked InsG3680 mutation manifest striatal synaptic transmission defects before weaning age and impaired juvenile social interaction, coinciding with the early onset of ASD symptoms. On the other hand, adult mice carrying the schizophrenia-linked R1117X mutation show profound synaptic defects in prefrontal cortex and social dominance behavior. Furthermore, we found differential Shank3 mRNA stability and SHANK1/2 upregulation in these two lines. These data demonstrate that different alleles of the same gene may have distinct phenotypes at molecular, synaptic, and circuit levels in mice, which may inform exploration of these relationships in human patients.

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Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects

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