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.
This is a preview of subscription content
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
Amso, D., Haas, S., Tenenbaum, E., Markant, J. & Sheinkopf, S. J. Bottom-up attention orienting in young children with autism. J. Aut. Dev. Disord. 44, 664–673 (2014).
Leekam, S. R., Nieto, C., Libby, S. J., Wing, L. & Gould, J. Describing the sensory abnormalities of children and adults with autism. J. Aut. Dev. Disord. 37, 894–910 (2007).
Wang, A. T. et al. Neural selectivity for communicative auditory signals in Phelan-McDermid syndrome. J. Neurodev. Disord. 8, 5 (2016).
Gogolla, N., Takesian, A. E., Feng, G., Fagiolini, M. & Hensch, T. K. Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron 83, 894–905 (2014).
Goncalves, J. T., Anstey, J. E., Golshani, P. & Portera-Cailliau, C. Circuit level defects in the developing neocortex of Fragile X mice. Nat. Neurosci. 16, 903–909 (2013).
Chao, H. T. et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468, 263–269 (2010).
Zhang, Y. et al. Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice. Nat. Neurosci. 17, 1701–1709 (2014).
Orefice, L. L. et al. Peripheral mechanosensory neuron dysfunction underlies tactile and behavioral deficits in mouse models of ASDs. Cell 166, 299–313 (2016).
Peca, J. et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437–442 (2011).
Naisbitt, S. et al. Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 23, 569–582 (1999).
Bozdagi, O. et al. Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol. Aut. 1, 15 (2010).
Mei, Y. et al. Adult restoration of Shank3 expression rescues selective autistic-like phenotypes. Nature 530, 481–484 (2016).
Wang, X. et al. Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism. Nat. Commun. 7, 11459 (2016).
Wang, X. et al. Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum. Mol. Genet. 20, 3093–3108 (2011).
Siegle, J. H., Pritchett, D. L. & Moore, C. I. Gamma-range synchronization of fast-spiking interneurons can enhance detection of tactile stimuli. Nat. Neurosci. 17, 1371–1379 (2014).
Luo, T. Z. & Maunsell, J. H. Neuronal modulations in visual cortex are associated with only one of multiple components of attention. Neuron 86, 1182–1188 (2015).
Goel, A. et al. Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible. Nat. Neurosci. 21, 1404–1411 (2018).
de la Rocha, J., Doiron, B., Shea-Brown, E., Josic, K. & Reyes, A. Correlation between neural spike trains increases with firing rate. Nature 448, 802–806 (2007).
Chen, T. W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295–300 (2013).
Doiron, B., Litwin-Kumar, A., Rosenbaum, R., Ocker, G. K. & Josic, K. The mechanics of state-dependent neural correlations. Nat. Neurosci. 19, 383–393 (2016).
Peron, S. P., Freeman, J., Iyer, V., Guo, C. & Svoboda, K. A cellular resolution map of barrel cortex activity during tactile behavior. Neuron 86, 783–799 (2015).
Crochet, S., Poulet, J. F., Kremer, Y. & Petersen, C. C. Synaptic mechanisms underlying sparse coding of active touch. Neuron 69, 1160–1175 (2011).
Yang, H., Kwon, S. E., Severson, K. S. & O’Connor, D. H. Origins of choice-related activity in mouse somatosensory cortex. Nat. Neurosci. 19, 127–134 (2016).
Kim, E. & Sheng, M. PDZ domain proteins of synapses. Nat. Rev. Neurosci. 5, 771–781 (2004).
Kouser, M. et al. Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission. J. Neurosci. 33, 18448–18468 (2013).
Cruikshank, S. J. et al. Thalamic control of layer 1 circuits in prefrontal cortex. J. Neurosci. 32, 17813–17823 (2012).
Moore, C. I. & Nelson, S. B. Spatio-temporal subthreshold receptive fields in the vibrissa representation of rat primary somatosensory cortex. J. Neurophysiol. 80, 2882–2892 (1998).
Wehr, M. & Zador, A. M. Balanced inhibition underlies tuning and sharpens spike timing in auditory cortex. Nature 426, 442–446 (2003).
Orefice, L. L. et al. Targeting peripheral somatosensory neurons to improve tactile-related phenotypes in ASD models. Cell 178, 867–886 e824 (2019).
Dimidschstein, J. et al. A viral strategy for targeting and manipulating interneurons across vertebrate species. Nat. Neurosci. 19, 1743–1749 (2016).
Sachidhanandam, S., Sermet, B. S. & Petersen, C. C. H. Parvalbumin-expressing GABAergic neurons in mouse barrel cortex contribute to gating a goal-directed sensorimotor transformation. Cell Rep. 15, 700–706 (2016).
Goffin, D., Brodkin, E. S., Blendy, J. A., Siegel, S. J. & Zhou, Z. Cellular origins of auditory event-related potential deficits in Rett syndrome. Nat. Neurosci. 17, 804–806 (2014).
Selby, L., Zhang, C. & Sun, Q. Q. Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation protein. Neurosci. Lett. 412, 227–232 (2007).
O’Neill, M. & Jones, R. S. Sensory-perceptual abnormalities in autism: a case for more research? J. Aut. Dev. Disord. 27, 283–293 (1997).
Marco, E. J., Hinkley, L. B., Hill, S. S. & Nagarajan, S. S. Sensory processing in autism: a review of neurophysiologic findings. Pediatr. Res. 69, 48R–54R (2011).
Lee, J. et al. Shank3-mutant mice lacking exon 9 show altered excitation/inhibition balance, enhanced rearing, and spatial memory deficit. Front. Cell. Neurosci. 9, 94 (2015).
Tu, J. C. et al. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 23, 583–592 (1999).
Peixoto, R. T., Wang, W., Croney, D. M., Kozorovitskiy, Y. & Sabatini, B. L. Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B -/- mice. Nat. Neurosci. 19, 716–724 (2016).
Rubenstein, J. L. & Merzenich, M. M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003).
Bolton, P. F. et al. Epilepsy in autism: features and correlates. J. Ment. Sci. 198, 289–294 (2011).
Thompson, K. J. et al. DREADD agonist 21 is an effective agonist for muscarinic-based DREADDs in vitro and in vivo. ACS Pharmacol. Transl. Sci. 1, 61–72 (2018).
Chen, Q. et al. Imaging neural activity using Thy1-GCaMP transgenic mice. Neuron 76, 297–308 (2012).
Truszkowski, T. L. A cellular mechanism for inverse effectiveness in multisensory integration. eLife 6, e25392 (2017).
Guizar-Sicairos, M., Thurman, S. T. & Fienup, J. R. Efficient subpixel image registration algorithms. Opt. Lett. 33, 156–158 (2008).
Kerlin, A. M., Andermann, M. L., Berezovskii, V. K. & Reid, R. C. Broadly tuned response properties of diverse inhibitory neuron subtypes in mouse visual cortex. Neuron 67, 858–871 (2010).
Komiyama, T. et al. Learning-related fine-scale specificity imaged in motor cortex circuits of behaving mice. Nature 464, 1182–1186 (2010).
Pachitariu, M., Stringer, C. & Harris, K. D. Robustness of spike deconvolution for neuronal calcium imaging. J. Neurosci. 38, 7976–7985 (2018).
Friedrich, J., Zhou, P. & Paninski, L. Fast online deconvolution of calcium imaging data. PLoS Comput. Biol. 13, e1005423 (2017).
Altman, D. G. & Bland, J. M. How to obtain the confidence interval from a P value. Brit. Med. J. 343, d2090 (2011).
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.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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.
About this article
Cite this article
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
Scientific Reports (2022)
Astrocytic Gap Junctions Contribute to Aberrant Neuronal Synchronization in a Mouse Model of MeCP2 Duplication Syndrome
Neuroscience Bulletin (2022)
Molecular Autism (2021)
Looking for consistency in an uncertain world: test-retest reliability of neurophysiological and behavioral readouts in autism
Journal of Neurodevelopmental Disorders (2021)
Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications
Journal of Neurodevelopmental Disorders (2021)