16p11.2 deletion mice exhibit compromised fronto-temporal connectivity, GABAergic dysfunction, and enhanced attentional ability

Openshaw, R. L. , Thomson, D. M., Bristow, G. C., Mitchell, E. J., Pratt, J. A., Morris, B. J. and Dawson, N. (2023) 16p11.2 deletion mice exhibit compromised fronto-temporal connectivity, GABAergic dysfunction, and enhanced attentional ability. Communications Biology, 6, 557. (doi: 10.1038/s42003-023-04891-2) (PMID:37225770) (PMCID:PMC10209099)

Abstract

Autism spectrum disorders are more common in males, and have a substantial genetic component. Chromosomal 16p11.2 deletions in particular carry strong genetic risk for autism, yet their neurobiological impact is poorly characterised, particularly at the integrated systems level. Here we show that mice reproducing this deletion (16p11.2 DEL mice) have reduced GABAergic interneuron gene expression (decreased parvalbumin mRNA in orbitofrontal cortex, and male-specific decreases in Gad67 mRNA in parietal and insular cortex and medial septum). Metabolic activity was increased in medial septum, and in its efferent targets: mammillary body and (males only) subiculum. Functional connectivity was altered between orbitofrontal, insular and auditory cortex, and between septum and hippocampus/subiculum. Consistent with this circuit dysfunction, 16p11.2 DEL mice showed reduced prepulse inhibition, but enhanced performance in the continuous performance test of attentional ability. Level 1 autistic individuals show similarly heightened performance in the equivalent human test, also associated with parietal, insular-orbitofrontal and septo-subicular dysfunction. The data implicate cortical and septal GABAergic dysfunction, and resulting connectivity changes, as the cause of pre-attentional and attentional changes in autism.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Morris, Professor Brian and Openshaw, Rebecca Louise
• Authors: Openshaw, R. L., Thomson, D. M., Bristow, G. C., Mitchell, E. J., Pratt, J. A., Morris, B. J., and Dawson, N.
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Communications Biology
• Publisher: Nature Research
• ISSN: 2399-3642
• ISSN (Online): 2399-3642
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Communications Biology 6: 557
• Publisher Policy: Reproduced under a Creative Commons License
• Data DOI: 10.5061/dryad.x69p8czp7

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
172418		Characterising mice syntenic for human 16p11.2 in relation to schizophrenia and autism. ID 13267	Brian Morris	Medical Research Council (MRC)	MR/N012704/1	Centre for Neuroscience