Background

Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurogenetic disorder caused by duplications of the maternal copy of this region. In addition to hypotonia, motor deficits, and language impairments, patients with Dup15q commonly meet the criteria for autism spectrum disorder and have a high prevalence of seizures. It is known from mouse models that synaptic impairments are a strong component of Dup15q pathophysiology; however, cellular phenotypes that relate to seizures are less clear. The development of patient-derived induced pluripotent stem cells provides a unique opportunity to study human neurons with the exact genetic disruptions that cause Dup15q.

Methods

Here, we explored electrophysiological phenotypes in induced pluripotent stem cell–derived neurons from 4 patients with Dup15q compared with 6 unaffected control subjects, 1 patient with a 15q11-q13 paternal duplication, and 3 patients with Angelman syndrome.

Results

We identified several properties of Dup15q neurons that could contribute to neuronal hyperexcitability and seizure susceptibility. Compared with control neurons, Dup15q neurons had increased excitatory synaptic event frequency and amplitude, increased density of dendritic protrusions, increased action potential firing, and decreased inhibitory synaptic transmission. Dup15q neurons also showed impairments in activity-dependent synaptic plasticity and homeostatic synaptic scaling. Finally, Dup15q neurons showed an increased frequency of spontaneous action potential firing compared with control neurons, in part due to disruption of KCNQ2 potassium channels.

Conclusions

Together, these data point to multiple electrophysiological mechanisms of hyperexcitability that may provide new targets for the treatment of seizures and other phenotypes associated with Dup15q.

中文翻译：

---

15q11-q13 重复综合征（一种自闭症的遗传形式）患者的诱导多能干细胞衍生神经元的过度兴奋表型

背景

染色体 15q11-q13 重复综合征 (Dup15q) 是由该区域的母体副本重复引起的神经遗传性疾病。除了肌张力减退、运动缺陷和语言障碍外，Dup15q 患者通常符合自闭症谱系障碍的标准，并且癫痫发作的患病率很高。从小鼠模型中得知，突触损伤是 Dup15q 病理生理学的重要组成部分；然而，与癫痫发作相关的细胞表型不太清楚。患者来源的诱导性多能干细胞的发展为研究具有导致 Dup15q 的确切遗传破坏的人类神经元提供了独特的机会。

方法

在这里，我们探索了来自 4 名 Dup15q 患者的诱导多能干细胞衍生神经元的电生理表型，与 6 名未受影响的对照组、1 名 15q11-q13 父系重复患者和 3 名 Angelman 综合征患者进行了比较。

结果

我们确定了 Dup15q 神经元的几个特性，这些特性可能导致神经元过度兴奋和癫痫易感性。与对照神经元相比，Dup15q 神经元的兴奋性突触事件频率和振幅增加，树突突起密度增加，动作电位放电增加，抑制性突触传递减少。Dup15q 神经元还表现出活动依赖性突触可塑性和稳态突触缩放的损伤。最后，与对照神经元相比，Dup15q 神经元显示自发动作电位放电频率增加，部分原因是 KCNQ2 钾通道中断。

结论

总之，这些数据指向过度兴奋的多种电生理机制，这些机制可能为癫痫发作和与 Dup15q 相关的其他表型的治疗提供新的靶点。