Abstract
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.
Highlights
Multiple genetic and environmental factors increase the risk for developing schizophrenia.[1]
PolyI:C is a synthetic analog of double-stranded RNA and it is recognized by toll-like receptor 3 (Tlr3), which, in turn activates the transcription factor RelA resulting in strong innate immune responses.[11]
The subventricular zone (SVZ) contains microglia that we found a significant genotype x polycytidylic acid (polyI):C x tone trials interaction are constitutively more activated than in non-neurogenic regions.[27]
Summary
Multiple genetic and environmental factors increase the risk for developing schizophrenia.[1]. A three-way ANOVA repeated measures showed a (SVZ), a neurogenic stem cell niche lining the lateral ventricle close significant main effect of tone-shock trials (day 1) regardless of the to the choroid plexus, a major route of exchange between blood and brain.[26] SVZ cells proliferate throughout life in rodents and genotype or treatment (F(2,66) = 142.33; P < 0.001; N = 8–11 per group; Supplementary Figure 1c). These data suggest all mice generate neuroblasts that move in the rostral migratory stream learned the fear association task .
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