Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia.
Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia.
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DOI：
10.1186/s13073-023-01203-5
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发表时间：
2023-07-28
期刊：
影响因子：
12.3
通讯作者：
中科院分区：
文献类型：
--
作者：
精神分裂症的尸检研究一致显示大脑皮层的树突棘减少，但这些缺陷的机制基础仍然未知。最近的全基因组关联研究和外显子组测序调查牵连突触基因和精神分裂症的疾病生物学过程。我们通过区分7名精神分裂症患者和7名健康受试者的iPSC产生人类皮质锥体神经元，量化不同皮质神经元亚型中的树突棘和突触，并进行转录组学研究以确定精神分裂症中差异调节的基因和异常细胞过程。皮质神经元表达第三层标记CUX1，但不表达第五层标记CTIP2，表现出显着减少树突棘密度在精神分裂症，反映在尸检研究的结果。iPSC衍生的皮层神经元中的转录组学实验表明，在全基因组关联和外显子组测序研究中，精神分裂症中的差异表达基因富集了与精神分裂症有关的基因。此外，精神分裂症遗传学研究中涉及的大多数差异表达基因在精神分裂症皮层神经元中的表达水平较低。差异表达基因的网络分析导致NRXN3作为枢纽基因的鉴定，后续实验显示精神分裂症神经元中NRXN3 204同种型的特异性减少。此外，精神分裂症神经元中NRXN3 204同种型的过表达挽救了皮质神经元中的棘和突触缺陷，而健康神经元中NRXN3 204的敲低表型模仿了精神分裂症皮质神经元中观察到的棘和突触缺陷。抗精神病药物氯氮平增加了精神分裂症皮层神经元NRXN3 204亚型的表达，并挽救了脊柱和突触密度缺陷。总之，我们在iPSC衍生的皮层神经元中的发现概括了精神分裂症尸检研究中的细胞类型特异性发现，并导致鉴定了调节精神分裂症神经元中突触缺陷的NRXN3的特定亚型。在线版本包含补充材料，可通过10.1186/s13073 - 023 - 01203 - 5获得。
Postmortem studies in schizophrenia consistently show reduced dendritic spines in the cerebral cortex but the mechanistic underpinnings of these deficits remain unknown. Recent genome-wide association studies and exome sequencing investigations implicate synaptic genes and processes in the disease biology of schizophrenia. We generated human cortical pyramidal neurons by differentiating iPSCs of seven schizophrenia patients and seven healthy subjects, quantified dendritic spines and synapses in different cortical neuron subtypes, and carried out transcriptomic studies to identify differentially regulated genes and aberrant cellular processes in schizophrenia. Cortical neurons expressing layer III marker CUX1, but not those expressing layer V marker CTIP2, showed significant reduction in dendritic spine density in schizophrenia, mirroring findings in postmortem studies. Transcriptomic experiments in iPSC-derived cortical neurons showed that differentially expressed genes in schizophrenia were enriched for genes implicated in schizophrenia in genome-wide association and exome sequencing studies. Moreover, most of the differentially expressed genes implicated in schizophrenia genetic studies had lower expression levels in schizophrenia cortical neurons. Network analysis of differentially expressed genes led to identification of NRXN3 as a hub gene, and follow-up experiments showed specific reduction of the NRXN3 204 isoform in schizophrenia neurons. Furthermore, overexpression of the NRXN3 204 isoform in schizophrenia neurons rescued the spine and synapse deficits in the cortical neurons while knockdown of NRXN3 204 in healthy neurons phenocopied spine and synapse deficits seen in schizophrenia cortical neurons. The antipsychotic clozapine increased expression of the NRXN3 204 isoform in schizophrenia cortical neurons and rescued the spine and synapse density deficits. Taken together, our findings in iPSC-derived cortical neurons recapitulate cell type-specific findings in postmortem studies in schizophrenia and have led to the identification of a specific isoform of NRXN3 that modulates synaptic deficits in schizophrenia neurons. The online version contains supplementary material available at 10.1186/s13073-023-01203-5.
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影响因子：
4.5
作者：
Choudhary, Ashwani;Peles, David;Stern, Shani
通讯作者：
Stern, Shani
DOI：
10.1111/j.1601-183x.2010.00656.x
发表时间：
2011-03
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
DeVito LM;Balu DT;Kanter BR;Lykken C;Basu AC;Coyle JT;Eichenbaum H
通讯作者：
Eichenbaum H
影响因子：
12.3
作者：
Baldi BF;Hoyer C;Le Novère N
通讯作者：
Le Novère N
DOI：
10.1016/j.mcn.2015.12.002
发表时间：
2016-06
期刊：
Molecular and cellular neurosciences
影响因子：
--
作者：
Habela CW;Song H;Ming GL
通讯作者：
Ming GL
影响因子：
3.3
作者：
Glausier, J. R.;Lewis, D. A.
通讯作者：
Lewis, D. A.