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J Neurosci. 2019 Jul 3;39(27):5299-5310. doi: 10.1523/JNEUROSCI.2529-18.2019. Epub 2019 May 6.

Deletion of Autism Risk Gene Shank3 Disrupts Prefrontal Connectivity.

Author information

1
Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems, Istituto Italiano di Tecnologia, 38068 Rovereto, Italy.
2
Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, 56126 Pisa, Italy.
3
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Neurotoxicology and Neuroendocrinology Section, 00161 Rome, Italy, and.
4
Department of Data Analysis, Ghent University, 9000 Ghent, Belgium.
5
Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems, Istituto Italiano di Tecnologia, 38068 Rovereto, Italy, alessandro.gozzi@iit.it.

Abstract

Mutations in the synaptic scaffolding protein SHANK3 are a major cause of autism and are associated with prominent intellectual and language deficits. However, the neural mechanisms whereby SHANK3 deficiency affects higher-order socio-communicative functions remain unclear. Using high-resolution functional and structural MRI in adult male mice, here we show that loss of Shank3 (Shank3B -/-) results in disrupted local and long-range prefrontal and frontostriatal functional connectivity. We document that prefrontal hypoconnectivity is associated with reduced short-range cortical projections density, and reduced gray matter volume. Finally, we show that prefrontal disconnectivity is predictive of social communication deficits, as assessed with ultrasound vocalization recordings. Collectively, our results reveal a critical role of SHANK3 in the development of prefrontal anatomy and function, and suggest that SHANK3 deficiency may predispose to intellectual disability and socio-communicative impairments via dysregulation of higher-order cortical connectivity.SIGNIFICANCE STATEMENT Mutations in the synaptic scaffolding protein SHANK3 are commonly associated with autism, intellectual, and language deficits. Previous research has linked SHANK3 deficiency to basal ganglia dysfunction, motor stereotypies, and social deficits. However, the neural mechanism whereby Shank3 gene mutations affects cortical functional connectivity and higher-order socio-communicative functions remain unclear. Here we show that loss of SHANK3 in mice results in largely disrupted functional connectivity and abnormal gray matter anatomy in prefrontal areas. We also show that prefrontal connectivity disruption is tightly linked to socio-communicative deficits. Our findings suggest that SHANK3 is a critical orchestrator of frontocortical function, and that disrupted connectivity of prefrontal areas may underpin socio-communicative impairments observed in SHANK3 mutation carriers.

KEYWORDS:

Phelan-McDermid syndrome; autism spectrum disorder; basal ganglia; functional connectivity; mouse; resting state fMRI

PMID:
31061091
PMCID:
PMC6607754
[Available on 2020-01-03]
DOI:
10.1523/JNEUROSCI.2529-18.2019

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