Developmental deficits of MGE-derived interneurons in the Cntnap2 knockout mouse model of autism spectrum disorder

Frontiers in Cell and Developmental Biology

Cell and Developmental Biology

Isabel Del Pino¹  Rhys Knowles²  Riccardo Natoli²  Noorya Yasmin Ahmed²  Yovina Sontani²  Lixinyu Liu²  Nathalie Dehorter²  Ulrike Schumann²  Yumeng Wang²  Nathan Reynolds²  Jiayu Wen²  Da Mi³  Yiming Yan³  Xiaohan Li³ 

[1] Institute of Neurosciences, Spanish National Research Council (CSIC), Sant Joan d’Alacant, Spain;The Australian National University, The John Curtin School of Medical Research, Canberra, ACT, Australia;Tsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, Beijing, China;

关键词: interneuron;    maturation;    striatum;    autism;    CNTNAP2;   

DOI  :  10.3389/fcell.2023.1112062

 received in 2022-11-30, accepted in 2023-01-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

Interneurons are fundamental cells for maintaining the excitation-inhibition balance in the brain in health and disease. While interneurons have been shown to play a key role in the pathophysiology of autism spectrum disorder (ASD) in adult mice, little is known about how their maturation is altered in the developing striatum in ASD. Here, we aimed to track striatal developing interneurons and elucidate the molecular and physiological alterations in the Cntnap2 knockout mouse model. Using Stereo-seq and single-cell RNA sequencing data, we first characterized the pattern of expression of Cntnap2 in the adult brain and at embryonic stages in the medial ganglionic eminence (MGE), a transitory structure producing most cortical and striatal interneurons. We found that Cntnap2 is enriched in the striatum, compared to the cortex, particularly in the developing striatal cholinergic interneurons. We then revealed enhanced MGE-derived cell proliferation, followed by increased cell loss during the canonical window of developmental cell death in the Cntnap2 knockout mice. We uncovered specific cellular and molecular alterations in the developing Lhx6-expressing cholinergic interneurons of the striatum, which impacts interneuron firing properties during the first postnatal week. Overall, our work unveils some of the mechanisms underlying the shift in the developmental trajectory of striatal interneurons which greatly contribute to the ASD pathogenesis.

【 授权许可】

Unknown   
Copyright © 2023 Ahmed, Knowles, Liu, Yan, Li, Schumann, Wang, Sontani, Reynolds, Natoli, Wen, Del Pino, Mi and Dehorter.