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16p11.2 deletion mice exhibit compromised fronto-temporal connectivity, GABAergic dysfunction, and enhanced
Rebecca L Openshaw1, David M Thomson2, Greg C Bristow3,4
1School of Psychology and Neuroscience, College of Medical, Veterinary and Life Sciences, University of Glasgow, Sir James Black Building, Glasgow, G12 8QQ, UK.
Communications Biology
|May 24, 2023
Summary
A specific genetic deletion linked to autism spectrum disorder (ASD) causes brain changes in mice, affecting GABAergic interneurons and brain connectivity, leading to altered attention abilities. These findings may explain attention deficits in individuals with ASD.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Autism spectrum disorders (ASD) exhibit a significant genetic basis, with chromosomal 16p11.2 deletions identified as a strong risk factor.
- The neurobiological underpinnings of 16p11.2 deletions, particularly at an integrated systems level, remain poorly understood.
Purpose of the Study:
- To investigate the neurobiological consequences of the 16p11.2 deletion in a mouse model.
- To explore the impact of this deletion on gene expression, metabolic activity, functional connectivity, and behavioral outcomes related to attention.
Main Methods:
- Utilized 16p11.2 deletion mouse models (16p11.2 DEL mice).
- Assessed GABAergic interneuron gene expression (parvalbumin, Gad67 mRNA) in specific brain regions.
- Measured metabolic activity in the medial septum and its efferent targets.
- Analyzed functional connectivity between cortical and subcortical regions.
- Evaluated behavioral performance using prepulse inhibition and the continuous performance test.
Main Results:
- 16p11.2 DEL mice displayed reduced GABAergic interneuron gene expression.
- Increased metabolic activity was observed in the medial septum and its targets (mammillary body, subiculum).
- Altered functional connectivity was found between orbitofrontal, insular, auditory cortex, and the septum-hippocampus/subiculum pathways.
- Mice showed reduced prepulse inhibition but enhanced performance on the continuous performance test, mirroring human findings in individuals with Level 1 ASD.
Conclusions:
- The 16p11.2 deletion is implicated in cortical and septal GABAergic dysfunction.
- Resulting alterations in brain connectivity contribute to pre-attentional and attentional deficits observed in autism spectrum disorder.
- This study provides a neurobiological framework for understanding the behavioral phenotypes associated with 16p11.2 deletions in ASD.
