Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Chemical Biology and Therapeutic Science Program, Broad Institute of MIT & Harvard, Cambridge, MA, USA.
Transl Psychiatry. 2019 Nov 28;9(1):321. doi: 10.1038/s41398-019-0660-x.
Human postmortem studies suggest a major role for abnormalities in GABAergic interneurons in the prefrontal cortex in schizophrenia. Cortical interneurons differentiated from induced pluripotent stem cells (iPSCs) of schizophrenia subjects showed significantly lower levels of glutamate decarboxylase 67 (GAD67), replicating findings from multiple postmortem studies, as well as reduced levels of synaptic proteins gehpyrin and NLGN2. Co-cultures of the interneurons with excitatory cortical pyramidal neurons from schizophrenia iPSCs showed reduced synaptic puncta density and lower action potential frequency. NLGN2 overexpression in schizophrenia neurons rescued synaptic puncta deficits while NLGN2 knockdown in healthy neurons resulted in reduced synaptic puncta density. Schizophrenia interneurons also had significantly smaller nuclear area, suggesting an innate oxidative stressed state. The antioxidant N-acetylcysteine increased the nuclear area in schizophrenia interneurons, increased NLGN2 expression and rescued synaptic deficits. These results implicate specific deficiencies in the synaptic machinery in cortical interneurons as critical regulators of synaptic connections in schizophrenia and point to a nexus between oxidative stress and NLGN2 expression in mediating synaptic deficits in schizophrenia.
人体尸检研究表明，精神分裂症患者前额叶皮层中 GABA 能中间神经元的异常在其中起着重要作用。精神分裂症患者诱导多能干细胞 (iPSC) 分化出的皮质中间神经元谷氨酸脱羧酶 67 (GAD67) 水平明显降低，这与多项尸检研究的结果一致，同时突触蛋白 gehpyrin 和 NLGN2 的水平也降低。将中间神经元与精神分裂症 iPSC 的兴奋性皮质锥体细胞共培养，显示突触小体密度降低，动作电位频率降低。在精神分裂症神经元中过表达 NLGN2 可挽救突触小体缺陷，而在健康神经元中敲低 NLGN2 则导致突触小体密度降低。精神分裂症中间神经元的核面积也明显较小，提示存在固有氧化应激状态。抗氧化剂 N-乙酰半胱氨酸可增加精神分裂症中间神经元的核面积，增加 NLGN2 的表达并挽救突触缺陷。这些结果表明，皮质中间神经元的突触机制存在特定缺陷，是精神分裂症中突触连接的关键调节因子，并指出氧化应激和 NLGN2 表达在介导精神分裂症中突触缺陷之间存在联系。
