Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-associated mutations
Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-associated mutations
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DOI：
10.1101/2022.11.02.514882
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发表时间：
2023-05
影响因子：
6.8
通讯作者：
Yara Hussein;Utkarsh Tripathi;Ashwani Choudhary;Ritu Nayak;David Peles;Idan Rosh;Jose Djamus;R. Spiegel;Tali Garin-Shkolnik;Shani Stern
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文献类型：
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作者：
Yara Hussein;Utkarsh Tripathi;Ashwani Choudhary;Ritu Nayak;David Peles;Idan Rosh;Jose Djamus;R. Spiegel;Tali Garin-Shkolnik;Shani Stern
自闭症谱系障碍（ASD）的主要特征是社会和感觉运动异常和重复的行为模式。据报道，超过数百个基因和数千个遗传变异是ASD的高度渗透和病因。这些突变中的许多导致合并症，如癫痫和智力残疾（ID）。在这项研究中，我们测量了来自基因GRIN 2B，SHANK 3，UBTF中有四种突变以及7q11.23区域染色体重复的患者的诱导多能干细胞（iPSC）的皮质神经元，并将其与来自一级亲属的神经元进行了比较。使用全细胞膜片钳，我们观察到，突变皮层神经元表现出过度兴奋性和早期成熟相比，控制线。这些变化的特征是钠电流增加，兴奋性突触后电流（EPSC）的幅度和速率增加，以及在早期细胞发育（分化后3-5周）中响应电流刺激的更多诱发动作电位。这些变化出现在所有不同的突变株系，连同以前报道的数据，表明早期成熟和过度兴奋可能是ASD皮层神经元的收敛表型。
Autism Spectrum Disorder (ASD) is characterized mainly by social and sensory-motor abnormal and repetitive behavior patterns. Over hundreds of genes and thousands of genetic variants were reported to be highly penetrant and causative of ASD. Many of these mutations cause comorbidities such as epilepsy and intellectual disabilities (ID). In this study, we measured cortical neurons derived from induced pluripotent stem cells (iPSCs) of patients with four mutations in the genes GRIN2B , SHANK3 , UBTF , as well as chromosomal duplication in the 7q11.23 region and compared them to neurons derived from a first-degree relative without the mutation. Using a whole-cell patch-clamp, we observed that the mutant cortical neurons demonstrated hyperexcitability and early maturation compared to control lines. These changes were characterized by increased sodium currents, increased amplitude and rate of excitatory postsynaptic currents (EPSCs), and more evoked action potentials in response to current stimulation in early-stage cell development (3–5 weeks post differentiation). These changes that appeared in all the different mutant lines, together with previously reported data, indicate that an early maturation and hyperexcitability may be a convergent phenotype of ASD cortical neurons.