NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy, and the latter is associated with excessive neuronal firing. NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/β/γ. Previous studies on cultured cells show that the short NRXN1β primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of NRXN1α deletions in human neurons. We recently derived induced pluripotent stem cells (iPSCs) from five controls and three ASD patients carrying NRXN1α+/- and showed increased calcium transients in patient neurons. In this study we investigated the electrophysiological properties of iPSC-derived cortical neurons in control and ASD patients carrying NRXN1α+/- using patch clamping. Whole genome RNA sequencing was carried out to further understand the potential underlying molecular mechanism. NRXN1α+/- cortical neurons were shown to display larger sodium currents, higher AP amplitude and accelerated depolarization time. RNASeq analyses revealed transcriptomic changes with significant upregulation glutamatergic synapse and ion channels/transporter activity including voltage-gated potassium channels (GRIN1, GRIN3B, SLC17A6, CACNG3, CACNA1A, SHANK1), which are likely to couple with the increased excitability in NRXN1α+/- cortical neurons. Together with recent evidence of increased calcium transients, our results showed that human NRXN1α+/- isoform deletions altered neuronal excitability and non-synaptic function, and NRXN1α+/- patient iPSCs may be used as an ASD model for therapeutic development with calcium transients and excitability as readouts.

中文翻译：

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NRXN1α+/- 与 ASD iPSC 衍生神经元的兴奋性增加有关

NRXN1 缺失被确定为自闭症谱系障碍 (ASD) 和其他神经发育障碍的主要罕见危险因素之一。ASD 与癫痫有 30% 的共病，后者与过度的神经元放电有关。NRXN1 编码数百种突触前神经粘附蛋白，分类为 NRXN1α/β/γ。以往对培养细胞的研究表明，短的 NRXN1β 主要发挥激发作用，而在患者中更常见的缺失的长 NRXN1α 涉及激发和抑制。然而，患者衍生的模型对于理解人类神经元中 NRXN1α 缺失的功能后果至关重要。我们最近从五名对照和三名携带 NRXN1α+/- 的 ASD 患者中获得诱导多能干细胞 (iPSC)，并显示患者神经元中钙瞬变增加。在这项研究中，我们使用膜片钳研究了携带 NRXN1α+/- 的对照和 ASD 患者中 iPSC 衍生的皮层神经元的电生理特性。进行全基因组 RNA 测序以进一步了解潜在的潜在分子机制。NRXN1α + / - 皮质神经元显示出更大的钠电流、更高的 AP 幅度和加速的去极化时间。RNASeq 分析显示转录组学变化显着上调谷氨酸能突触和离子通道/转运蛋白活性，包括电压门控钾通道（GRIN1、GRIN3B、SLC17A6、CACNG3、CACNA1A、SHANK1），这可能与 NRXN1α 的兴奋性增加 + / -皮层神经元。连同最近的钙瞬变增加的证据，