Hyperexcitable Phenotypes in Induced Pluripotent Stem Cell-Derived Neurons From Patients With 15q11-q13 Duplication Syndrome, a Genetic Form of Autism.
Hyperexcitable Phenotypes in Induced Pluripotent Stem Cell-Derived Neurons From Patients With 15q11-q13 Duplication Syndrome, a Genetic Form of Autism.
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DOI：
10.1016/j.biopsych.2021.07.018
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发表时间：
2021-12-01
影响因子：
10.6
通讯作者：
Levine ES
中科院分区：
文献类型：
--
作者：
Fink JJ;Schreiner JD;Bloom JE;James J;Baker DS;Robinson TM;Lieberman R;Loew LM;Chamberlain SJ;Levine ES
染色体15 q11-q13复制综合征（Dup 15 q）是由该区域的母体拷贝复制引起的神经遗传性疾病。除了张力减退、运动缺陷和语言障碍外，Dup 15 q患者通常符合自闭症谱系障碍（ASD）的标准，并且癫痫发作的患病率很高。从小鼠模型中已知，突触损伤是Dup 15 q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尚不清楚。患者源性诱导多能干细胞（iPSC）的开发为研究具有导致Dup 15 q的确切遗传破坏的人类神经元提供了独特的机会。在这里，我们探索了来自四名Dup 15 q患者的iPSC衍生神经元的电生理表型，与六名未受影响的对照组，一名15 q11-q13父系重复的患者和三名Angelman综合征患者进行了比较。我们确定了Dup 15 q神经元的几个属性，可能有助于神经元的过度兴奋性和癫痫发作的易感性。与对照组相比，Dup 15 q神经元兴奋性突触事件频率和振幅增加，树突突起密度增加，沿着动作电位放电增加，抑制性突触传递减少。Dup 15 q神经元也表现出活动依赖性突触可塑性和稳态突触缩放的损害。最后，Dup 15 q神经元表现出自发动作电位放电的频率增加，与对照神经元相比，部分原因是KCNQ 2钾通道的破坏。这些数据共同指向了过度兴奋的多种电生理机制，这些机制可能为治疗癫痫发作和与Dup 15 q相关的其他表型提供新的靶点。
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, Dup15q patients commonly meet the criteria for autism spectrum disorder (ASD) 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 (iPSCs) provides a unique opportunity to study human neurons with the exact genetic disruptions that cause Dup15q. Here, we explored electrophysiological phenotypes in iPSC-derived neurons from four Dup15q patients compared to six unaffected controls, one patient with a 15q11-q13 paternal duplication, and three Angelman syndrome patients. We identified several properties of Dup15q neurons that could contribute to neuronal hyperexcitability and seizure susceptibility. Compared to controls, Dup15q neurons had increased excitatory synaptic event frequency and amplitude and increased density of dendritic protrusions, along with 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 to control neurons, in part due to disruption of KCNQ2 potassium channels. 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.
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