Identifying foetal forebrain interneurons as a target for monogenic autism risk factors and the polygenic 16p11.2 microdeletion

BMC Neuroscience

Research

Sandra Martin Lorenzo¹  Yann Herault¹  Zrinko Kozic²  David J. Price²  Anna Sumera²  Peter C. Kind²  Sam A. Booker²  Thomas Pratt²  James M. Clegg²  Owen Dando²  Yifei Yang³  Idoia Quintana-Urzainqui⁴ 

[1] CNRS, Université de Strasbourg, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire, IGBMC, 1 rue Laurent Fries, 67404, Illkirch, France;Simons Initiative for the Developing Brain, The University of Edinburgh, 15 George Square, EH8 9XD, Edinburgh, United Kingdom;Centre for Discovery Brain Sciences, The University of Edinburgh, 15 George Square, EH8 9XD, Edinburgh, United Kingdom;Simons Initiative for the Developing Brain, The University of Edinburgh, 15 George Square, EH8 9XD, Edinburgh, United Kingdom;Centre for Discovery Brain Sciences, The University of Edinburgh, 15 George Square, EH8 9XD, Edinburgh, United Kingdom;Department of Brain Sciences, Imperial College London, W12 0NN, London, United Kingdom;Simons Initiative for the Developing Brain, The University of Edinburgh, 15 George Square, EH8 9XD, Edinburgh, United Kingdom;Centre for Discovery Brain Sciences, The University of Edinburgh, 15 George Square, EH8 9XD, Edinburgh, United Kingdom;Developmental Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69012, Heidelberg, Germany;

关键词: Development;    Telencephalon;    Autism;    Genetics;    Single cell transcriptomics;    GABAergic;    Human;    Rat;    Electrophysiology;    AIS;   

DOI  :  10.1186/s12868-022-00771-3

 received in 2022-09-21, accepted in 2022-12-21,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundAutism spectrum condition or ‘autism’ is associated with numerous genetic risk factors including the polygenic 16p11.2 microdeletion. The balance between excitatory and inhibitory neurons in the cerebral cortex is hypothesised to be critical for the aetiology of autism making improved understanding of how risk factors impact on the development of these cells an important area of research. In the current study we aim to combine bioinformatics analysis of human foetal cerebral cortex gene expression data with anatomical and electrophysiological analysis of a 16p11.2+/- rat model to investigate how genetic risk factors impact on inhibitory neuron development.MethodsWe performed bioinformatics analysis of single cell transcriptomes from gestational week (GW) 8–26 human foetal prefrontal cortex and anatomical and electrophysiological analysis of 16p11.2+/- rat cerebral cortex and hippocampus at post-natal day (P) 21.ResultsWe identified a subset of human interneurons (INs) first appearing at GW23 with enriched expression of a large fraction of risk factor transcripts including those expressed from the 16p11.2 locus. This suggests the hypothesis that these foetal INs are vulnerable to mutations causing autism. We investigated this in a rat model of the 16p11.2 microdeletion. We found no change in the numbers or position of either excitatory or inhibitory neurons in the somatosensory cortex or CA1 of 16p11.2+/- rats but found that CA1 Sst INs were hyperexcitable with an enlarged axon initial segment, which was not the case for CA1 pyramidal cells.LimitationsThe human foetal gene expression data was acquired from cerebral cortex between gestational week (GW) 8 to 26. We cannot draw inferences about potential vulnerabilities to genetic autism risk factors for cells not present in the developing cerebral cortex at these stages. The analysis 16p11.2+/- rat phenotypes reported in the current study was restricted to 3-week old (P21) animals around the time of weaning and to a single interneuron cell-type while in human 16p11.2 microdeletion carriers symptoms likely involve multiple cell types and manifest in the first few years of life and on into adulthood.ConclusionsWe have identified developing interneurons in human foetal cerebral cortex as potentially vulnerable to monogenic autism risk factors and the 16p11.2 microdeletion and report interneuron phenotypes in post-natal 16p11.2+/- rats.

【 授权许可】

CC BY   
© The Author(s) 2022

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