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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Raw data is available from the corresponding author upon request.
The custom routines for image analysis written in MATLAB are available on GitHub (https://github.com/cdeister/imageAnalysis_gui) and from the corresponding author upon request.
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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.).
The authors declare no competing interests.
Peer review information Nature Neuroscience thanks D. Feldman and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Supplementary Figures 1–8
Spontaneous Neuronal Activity of Somatosensory Cortex from Shank3Bfl/fl Mice Injected with AAV-Dlx5/6-ΔCre-mKate2 and AAV-CaMKII-GCaMP6.
Spontaneous Neuronal Activity of Somatosensory Cortex from Shank3Bfl/fl Mice Injected with AAV-Dlx5/6-Cre-mKate2 and AAV-CaMKII-GCaMP6.
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Chen, Q., Deister, C.A., Gao, X. et al. Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD. Nat Neurosci 23, 520–532 (2020). https://doi.org/10.1038/s41593-020-0598-6
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