Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone.
Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone.
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DOI：
10.1038/s41537-018-0057-5
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发表时间：
2018-07-23
影响因子：
5.4
通讯作者：
Szele FG
中科院分区：
文献类型：
--
作者：
Al-Shammari AR;Bhardwaj SK;Musaelyan K;Srivastava LK;Szele FG
精神分裂症是一种神经发育障碍，可能由环境和遗传风险因素引起，但这些风险因素之间的功能相互作用尚不清楚。我们验证了一种假设，即Dtnbp1基因突变和出生后暴露于病毒模拟PolyI：C会导致成年后精神分裂症相关行为的改变，并介导PolyI：C诱导的脑室下区(SVZ)炎症。成年Sandy(SDY，Dtnbp1突变体)小鼠出生后早期注射PolyI：C后，对惊吓的脉冲前抑制减少，运动减少，在新物体识别方面存在缺陷。PolyI：C在SVZ中诱导了典型的免疫反应；它增加了其Toll样受体3(TLR3)及其下游转录因子RelA和Sp1的mRNA表达。PolyI：C还增加了SVZ Dtnbp1mRNA的表达，表明dybindin-1调节免疫反应。在SDY小鼠中，dybindin-1的缺失阻断了PolyI：C诱导的SVZ中TLR3、RelA和Sp1mRNA表达的增加。在SVZ来源的SDY神经球中过表达Dtnbp1可挽救TLR3、RelA和Sp1mRNA的表达，支持dybindin-1和PolyI：C诱导的炎症之间的功能相互作用。免疫组织化学显示，出生后SDY小鼠SVZ的Iba1+免疫细胞密度高于WT小鼠。PolyI：C不改变SDY小鼠SVZIBA1+细胞密度，但增加CD45+/IBA1−细胞数。最后，在SDY小鼠中注射PolyI：C，而不是在WT小鼠中注射PolyI：C可以减少出生后和成年SVZ的增殖。总之，我们展示了精神分裂症相关的dybindin-1基因和对PolyI：C的免疫反应之间的新的功能相互作用。这项工作揭示了由于遗传易感性和暴露于环境精神分裂症危险因素而放大的异常的分子基础。
Schizophrenia is a neurodevelopmental disorder likely caused by environmental and genetic risk factors but functional interactions between the risk factors are unclear. We tested the hypothesis that dysbindin-1 (Dtnbp1) gene mutation combined with postnatal exposure to viral mimetic polyI:C results in schizophrenia-related behavioural changes in adulthood, and mediates polyI:C-induced inflammation in the subventricular zone (SVZ). Adult Sandy (Sdy, Dtnbp1 mutant) mice given early postnatal polyI:C injections displayed reduced prepulse inhibition of startle, reduced locomotion and deficits in novel object recognition. PolyI:C induced a canonical immune response in the SVZ; it increased mRNA expression of its toll-like receptor 3 (Tlr3) and downstream transcription factors RelA and Sp1. PolyI:C also increased SVZ Dtnbp1 mRNA expression, suggesting dysbindin-1 regulates immune responses. Dysbindin-1 loss in Sdy mice blocked the polyI:C-induced increases in mRNA expression of Tlr3, RelA and Sp1 in the SVZ. Dtnbp1 overexpression in SVZ-derived Sdy neurospheres rescued Tlr3, RelA and Sp1 mRNA expression supporting a functional interaction between dysbindin-1 and polyI:C-induced inflammation. Immunohistochemistry showed higher Iba1+ immune cell density in the SVZ of Sdy mice than in WT postnatally. PolyI:C did not alter SVZ Iba1+ cell density but increased CD45+/Iba1− cell numbers in the SVZ of Sdy mice. Finally, polyI:C injections in Sdy, but not WT mice reduced postnatal and adult SVZ proliferation. Together, we show novel functional interactions between the schizophrenia-relevant dysbindin-1 gene and the immune response to polyI:C. This work sheds light on the molecular basis for amplified abnormalities due to combined genetic predisposition and exposure to environmental schizophrenia risk factors.
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