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）是由于神经发育受到破坏/改变而引起的持续性疾病。ASD多因素病因及其多种合并症增加了识别其根本原因的难度，从而阻碍了有效疗法的发展。来自动物和人类研究的越来越多的证据表明，表达小白蛋白（PV）的抑制性中间神经元功能的改变是某些形式的ASD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）与皮层网络活动的调节密切相关。它们的特殊连通性模式，即它们优先靶向锥体细胞的周边区域和轴突起始节段，以及它们的相互连接，使PVALB神经元能够精确控制例如尖峰时序，从而导致在γ范围内产生和调节节律，这对于感觉知觉和注意力很重要。新方法如诱导多能干细胞（iPSC）基因组编辑技术（CRISPR / Cas9）已被证明是获得神经发育和/或神经退行性疾病和神经精神疾病的机械方法的有价值的工具。这样的技术进步使得从iPSC产生PVALB神经元成为可能。这些神经元的标签将允许在发育过程中遵循其命运，从前体细胞到分化的（和功能性的）PVALB神经元。同样，使用来自健康供体的iPSC或具有ASD风险基因已知突变的ASD患者，也可以更好地了解PVALB神经元的功能。在本概念文件中，简要讨论了有望更好地理解PVALB神经元功能的策略。我们设想，这种基于iPSC的方法与新兴的（遗传）技术相结合，可能提供机会详细研究PVALB神经元和PV在“离体神经发育”过程中的作用。