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.
Original language | English |
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Article number | 15 |
Number of pages | 11 |
Journal | Npj Schizophrenia |
Volume | 4 |
DOIs | |
Publication status | Published - 23 Jul 2018 |
Keywords
- Brain-barrier permeability
- Nf-kappa-b
- Prefrontal cortex
- Hippocampal-formation
- Messenger-rna
- Microglia
- Expression
- Infection
- Dtnbp1
- Sp1