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.

精神分裂症是一种可能由环境和遗传危险因素引起的神经发育障碍，但危险因素之间的功能相互作用尚不清楚。我们测试了假说dysbindin-1（Dtnbp1）基因突变与出生后暴露于病毒模拟polyI：C的组合会导致精神分裂症相关的成年行为改变，并介导polyI：C引起的脑室下区域（SVZ）的炎症。产后早期注射polyI：C的成年桑迪（Sdy，Dtnbp1突变体）小鼠表现出降低的惊吓前脉冲抑制，运动和新物体识别缺陷。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）和下游转录因子RelA和Sp1。PolyI：C还增加了SVZ Dtnbp1 mRNA的表达，表明dysbindin-1调节免疫反应。Sdy小鼠中Dysbindin-1的丢失阻止了polyI：C诱导的SVZ中Tlr3，RelA和Sp1 mRNA表达的增加。Dtnbp1过量表达在SVZ衍生的Sdy神经球中拯救了Tlr3，RelA和Sp1支持dysbindin-1和polyI：C诱导的炎症之间功能相互作用的mRNA表达。免疫组织化学显示，Sdy小鼠的SVZ中的Iba1 +免疫细胞密度高于出生后的WT。PolyI：C不会改变SVZ Iba1 +细胞密度，但会增加Sdy小鼠SVZ中的CD45 + / Iba1-细胞数量。最后，在Sdy中注射polyI：C，但在WT小鼠中未注射，降低了出生后和成年SVZ的增殖。在一起，我们显示精神分裂症相关的dysbindin-1基因和对polyI：C的免疫反应之间的新型功能相互作用。这项工作在分子基础上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导致的异常放大。