Identifying developing interneurons as a potential target for multiple genetic autism risk factors in human and rodent forebrain-猫眼课题宝

DOI：

10.1101/2021.06.03.446920

发表时间：

2021-06

期刊：

bioRxiv

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Yifei Yang;Sam A. Booker;James M. Clegg;Idoia Quintana Urzainqui;Anna Sumera;Zrinko Kozić;O. Dando;Sandra Martin Lorenzo;Y. Hérault;P. Kind;D. Price;T. Pratt

自闭症谱系障碍或“自闭症”与许多单基因和多基因遗传风险因素有关，包括多基因16p11.2微缺失。一个核心问题是什么神经细胞受到影响。为了系统地研究，我们分析了来自妊娠周（GW）8-26人胎儿前额叶皮质的单细胞转录组，并鉴定了首先出现在GW 23的中间神经元（IN）的子集，其具有不成比例的大部分风险因子转录本的富集表达。这表明了这样一种假设，即这些IN不成比例地容易受到导致自闭症的突变的影响。我们在16p11.2微缺失的大鼠模型中对此进行了研究。我们发现，无论是兴奋性或抑制性神经元的数量或位置的变化在体感皮层或CA 1的16p11.2+/-大鼠，但发现CA 1 Sst INs过度兴奋与扩大轴突起始段，这不是CA 1锥体细胞的情况。这项研究提示更深入的调查，作为自闭症遗传风险因素的收敛目标。

Autism spectrum condition or ‘autism’ is associated with numerous monogenic and polygenic genetic risk factors including the polygenic 16p11.2 microdeletion. A central question is what neural cells are affected. To systematically investigate we analysed single cell transcriptomes from gestational week (GW) 8-26 human foetal prefrontal cortex and identified a subset of interneurons (INs) first appearing at GW23 with enriched expression of a disproportionately large fraction of risk factor transcripts. This suggests the hypothesis that these INs are disproportionately 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. This study prompts deeper investigation of IN development as a convergent target for autism genetic risk factors.

Identifying developing interneurons as a potential target for multiple genetic autism risk factors in human and rodent forebrain

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