DataSheet1_Developmental deficits of MGE-derived interneurons in the Cntnap2 knockout mouse model of autism spectrum disorder.PDF

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.

中间神经元（Interneurons）是维持大脑在健康与疾病状态下兴奋-抑制平衡的核心细胞。尽管已有研究证实，成年小鼠体内的中间神经元在自闭症谱系障碍（ASD）的病理生理过程中发挥关键作用，但目前学界对自闭症谱系障碍模型小鼠发育中的纹状体的中间神经元成熟过程如何发生改变仍知之甚少。本研究旨在追踪发育纹状体中的中间神经元，并阐明Cntnap2基因敲除小鼠模型中存在的分子与生理学改变。本研究利用Stereo-seq与单细胞RNA测序（single-cell RNA sequencing）数据，首先解析了成年大脑以及胚胎阶段内侧神经节隆起（MGE）——一种可产生绝大多数皮质与纹状体中间神经元的暂时性结构——中Cntnap2的表达模式。研究发现，与皮质相比，Cntnap2在纹状体中富集，尤其是在发育中的纹状体胆碱能中间神经元内。随后我们发现，Cntnap2基因敲除小鼠体内，内侧神经节隆起来源的细胞增殖能力增强，且在发育性细胞死亡的典型窗口期内细胞丢失量增加。我们还揭示了发育中纹状体表达Lhx6的胆碱能中间神经元所存在的特异性细胞与分子改变，这类改变会在出生后第一周影响中间神经元的放电特性。综上，本研究揭示了纹状体中间神经元发育轨迹偏移的部分潜在机制，而这类偏移会极大地促进自闭症谱系障碍的发病进程。