Autism spectrum disorders (ASD) are persistent conditions resulting from disrupted/altered neurodevelopment. ASD multifactorial etiology-and its numerous comorbid conditions-heightens the difficulty in identifying its underlying causes, thus obstructing the development of effective therapies. Increasing evidence from both animal and human studies suggests an altered functioning of the parvalbumin (PV)-expressing inhibitory interneurons as a common and possibly unifying pathway for some forms of ASD. PV-expressing interneurons (short: PVALB neurons) are critically implicated in the regulation of cortical networks' activity. Their particular connectivity patterns, i.e., their preferential targeting of perisomatic regions and axon initial segments of pyramidal cells, as well as their reciprocal connections, enable PVALB neurons to exert a fine-tuned control of, e.g., spike timing, resulting in the generation and modulation of rhythms in the gamma range, which are important for sensory perception and attention.New methodologies such as induced pluripotent stem cells (iPSC) and genome-editing techniques (CRISPR/Cas9) have proven to be valuable tools to get mechanistic insight in neurodevelopmental and/or neurodegenerative and neuropsychiatric diseases. Such technological advances have enabled the generation of PVALB neurons from iPSC. Tagging of these neurons would allow following their fate during the development, from precursor cells to differentiated (and functional) PVALB neurons. Also, it would enable a better understanding of PVALB neuron function, using either iPSC from healthy donors or ASD patients with known mutations in ASD risk genes. In this concept paper, the strategies hopefully leading to a better understanding of PVALB neuron function(s) are briefly discussed. We envision that such an iPSC-based approach combined with emerging (genetic) technologies may offer the opportunity to investigate in detail the role of PVALB neurons and PV during "neurodevelopment ex vivo."

中文翻译：

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使用 iPSC 分析小白蛋白中间神经元：自闭症谱系障碍 (ASD) 的挑战和前景。


自闭症谱系障碍 (ASD) 是由神经发育破坏/改变引起的持续性疾病。自闭症谱系障碍 (ASD) 的多因素病因及其众多合并症，加大了识别其根本原因的难度，从而阻碍了有效疗法的开发。来自动物和人类研究的越来越多证据表明，表达小白蛋白 (PV) 的抑制性中间神经元的功能发生了改变，这是某些形式的 ASD 的常见且可能统一的途径。表达 PV 的中间神经元（简称：PVALB 神经元）与皮质网络活动的调节密切相关。它们特定的连接模式，即它们对锥体细胞的周围区域和轴突初始段的优先靶向，以及它们的相互连接，使 PVALB 神经元能够对例如尖峰时间进行微调控制，从而产生和伽玛范围内节律的调节，这对于感官知觉和注意力非常重要。诱导多能干细胞 (iPSC) 和基因组编辑技术 (CRISPR/Cas9) 等新方法已被证明是获得神经发育机制洞察的宝贵工具。和/或神经退行性疾病和神经精神疾病。这些技术进步使得 iPSC 能够生成 PVALB 神经元。对这些神经元进行标记可以跟踪它们在发育过程中的命运，从前体细胞到分化的（和功能性的）PVALB 神经元。此外，它还可以使用来自健康捐赠者的 iPSC 或具有已知 ASD 风险基因突变的 ASD 患者的 iPSC 来更好地了解 PVALB 神经元功能。 在这篇概念论文中，简要讨论了希望能够更好地理解 PVALB 神经元功能的策略。我们设想，这种基于 iPSC 的方法与新兴（遗传）技术相结合可能会提供机会来详细研究 PVALB 神经元和 PV 在“离体神经发育”过程中的作用。"