Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD
- 2 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Neuroscience
- Vol. 23 (4), 520-532
- https://doi.org/10.1038/s41593-020-0598-6
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (F32MH100749, R01MH097104, P50MH094271)
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01NS045130)
This publication has 49 references indexed in Scilit:
- Thalamic Control of Layer 1 Circuits in Prefrontal CortexJournal of Neuroscience, 2012
- Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3Human Molecular Genetics, 2011
- Sensory Processing in Autism: A Review of Neurophysiologic FindingsPediatric Research, 2011
- Epilepsy in autism: features and correlatesThe British Journal of Psychiatry, 2011
- Synaptic Mechanisms Underlying Sparse Coding of Active TouchNeuron, 2011
- Shank3 mutant mice display autistic-like behaviours and striatal dysfunctionNature, 2011
- Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communicationMolecular Autism, 2010
- Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypesNature, 2010
- Broadly Tuned Response Properties of Diverse Inhibitory Neuron Subtypes in Mouse Visual CortexNeuron, 2010
- Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation proteinNeuroscience Letters, 2007