Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD

Qian Chen; Christopher A. Deister; Xian Gao; Baolin Guo; Taylor Lynn-Jones; Naiyan Chen; Michael F. Wells; Runpeng Liu; Michael J. Goard; Jordane Dimidschstein; Shijing Feng; Yiwu Shi; Weiping Liao; Zhonghua Lu; Gord Fishell; Christopher I. Moore; Guoping Feng

doi:10.1038/s41593-020-0598-6

Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD

Qian Chen, Christopher A. Deister, Xian Gao, Baolin Guo, Taylor Lynn-Jones, Naiyan Chen, Michael F. Wells, Runpeng Liu, Michael J. Goard, Jordane Dimidschstein, Shijing Feng, Yiwu Shi, Weiping Liao, Zhonghua Lu, Gord Fishell, Christopher I. Moore, Guoping Feng

Center for Genomics and Systems Biology

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

Abstract

Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B^−/− mouse model of ASD. Male and female Shank3B^−/− mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions.

Original language	English (US)
Pages (from-to)	520-532
Number of pages	13
Journal	Nature Neuroscience
Volume	23
Issue number	4
DOIs	https://doi.org/10.1038/s41593-020-0598-6
State	Published - Apr 1 2020

ASJC Scopus subject areas

Neuroscience(all)

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10.1038/s41593-020-0598-6

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Chen, Q., Deister, C. A., Gao, X., Guo, B., Lynn-Jones, T., Chen, N., Wells, M. F., Liu, R., Goard, M. J., Dimidschstein, J., Feng, S., Shi, Y., Liao, W., Lu, Z., Fishell, G., Moore, C. I., & Feng, G. (2020). Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD. Nature Neuroscience, 23(4), 520-532. https://doi.org/10.1038/s41593-020-0598-6

Chen, Q, Deister, CA, Gao, X, Guo, B, Lynn-Jones, T, Chen, N, Wells, MF, Liu, R, Goard, MJ, Dimidschstein, J, Feng, S, Shi, Y, Liao, W, Lu, Z, Fishell, G, Moore, CI & Feng, G 2020, 'Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD', Nature Neuroscience, vol. 23, no. 4, pp. 520-532. https://doi.org/10.1038/s41593-020-0598-6

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title = "Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD",

abstract = "Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B−/− mouse model of ASD. Male and female Shank3B−/− mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions.",

author = "Qian Chen and Deister, {Christopher A.} and Xian Gao and Baolin Guo and Taylor Lynn-Jones and Naiyan Chen and Wells, {Michael F.} and Runpeng Liu and Goard, {Michael J.} and Jordane Dimidschstein and Shijing Feng and Yiwu Shi and Weiping Liao and Zhonghua Lu and Gord Fishell and Moore, {Christopher I.} and Guoping Feng",

note = "Funding Information: We thank J. Wilde, A. Krol, M. G. Chen, M. Hu and members of the Feng Lab for helpful discussions. We thank D. A. Scott, S. Allsop, B. Clear and T. Dalia for technical support. We thank the Varanasi Family and R. Buxton for supporting our autism research. This work was supported by the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, Nancy Lurie Marks Family Foundation, the Poitras Center for Psychiatric Disorders Research at the McGovern Institute for Brain Research at MIT, Shenzhen Overseas Innovation Team Project No. KQTD20140630180249366 (Z.L.); Guangdong Innovative and Entrepreneurial Research Team Program No. 2014ZT05S020 (Z.L.) and the National Institutes of Health R01MH097104 (G. Feng), NIMH Conte Center grant P50MH094271 (G. Feng), F32MH100749 (C.A.D.) and R01NS045130 (C.I.M.). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2020",

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doi = "10.1038/s41593-020-0598-6",

language = "English (US)",

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T1 - Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD

AU - Chen, Qian

AU - Deister, Christopher A.

AU - Gao, Xian

AU - Guo, Baolin

AU - Lynn-Jones, Taylor

AU - Chen, Naiyan

AU - Wells, Michael F.

AU - Liu, Runpeng

AU - Goard, Michael J.

AU - Dimidschstein, Jordane

AU - Feng, Shijing

AU - Shi, Yiwu

AU - Liao, Weiping

AU - Lu, Zhonghua

AU - Fishell, Gord

AU - Moore, Christopher I.

AU - Feng, Guoping

N1 - Funding Information: We thank J. Wilde, A. Krol, M. G. Chen, M. Hu and members of the Feng Lab for helpful discussions. We thank D. A. Scott, S. Allsop, B. Clear and T. Dalia for technical support. We thank the Varanasi Family and R. Buxton for supporting our autism research. This work was supported by the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, Nancy Lurie Marks Family Foundation, the Poitras Center for Psychiatric Disorders Research at the McGovern Institute for Brain Research at MIT, Shenzhen Overseas Innovation Team Project No. KQTD20140630180249366 (Z.L.); Guangdong Innovative and Entrepreneurial Research Team Program No. 2014ZT05S020 (Z.L.) and the National Institutes of Health R01MH097104 (G. Feng), NIMH Conte Center grant P50MH094271 (G. Feng), F32MH100749 (C.A.D.) and R01NS045130 (C.I.M.). Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2020/4/1

Y1 - 2020/4/1

N2 - Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B−/− mouse model of ASD. Male and female Shank3B−/− mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions.

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Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD

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