Department of Cognitive Neurosciences, Radboudumc, Donders Institute for Brain Cognition and Behaviour, 6525 HR Nijmegen, the Netherlands.
Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway; NORMENT, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway.
Cell Rep. 2022 May 3;39(5):110790. doi: 10.1016/j.celrep.2022.110790.
Heterozygous loss-of-function (LoF) mutations in SETD1A, which encodes a subunit of histone H3 lysine 4 methyltransferase, cause a neurodevelopmental syndrome and increase the risk for schizophrenia. Using CRISPR-Cas9, we generate excitatory/inhibitory neuronal networks from human induced pluripotent stem cells with a SETD1A heterozygous LoF mutation (SETD1A). Our data show that SETD1A haploinsufficiency results in morphologically increased dendritic complexity and functionally increased bursting activity. This network phenotype is primarily driven by SETD1A haploinsufficiency in glutamatergic neurons. In accordance with the functional changes, transcriptomic profiling reveals perturbations in gene sets associated with glutamatergic synaptic function. At the molecular level, we identify specific changes in the cyclic AMP (cAMP)/Protein Kinase A pathway pointing toward a hyperactive cAMP pathway in SETD1A neurons. Finally, by pharmacologically targeting the cAMP pathway, we are able to rescue the network deficits in SETD1A cultures. Our results demonstrate a link between SETD1A and the cAMP-dependent pathway in human neurons.
SETD1A 基因编码组蛋白 H3 赖氨酸 4 甲基转移酶的一个亚基，其杂合功能丧失（LoF）突变会导致神经发育综合征，并增加精神分裂症的风险。我们使用 CRISPR-Cas9 技术，从携带 SETD1A 杂合 LoF 突变（SETD1A）的人类诱导多能干细胞中生成兴奋性/抑制性神经元网络。我们的数据表明，SETD1A 部分不足会导致树突复杂性的形态增加和爆发活动的功能增加。这种网络表型主要是由谷氨酸能神经元中的 SETD1A 部分不足驱动的。与功能变化一致，转录组谱分析显示与谷氨酸能突触功能相关的基因集受到干扰。在分子水平上，我们发现 cAMP/蛋白激酶 A 通路中的特定变化指向 SETD1A 神经元中 cAMP 通路的过度活跃。最后，通过靶向 cAMP 通路的药理学方法，我们能够挽救 SETD1A 培养物中的网络缺陷。我们的结果表明，SETD1A 与人类神经元中的 cAMP 依赖性通路之间存在联系。
