Send to

Choose Destination
NPJ Schizophr. 2018 Jul 23;4(1):15. doi: 10.1038/s41537-018-0057-5.

Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone.

Author information

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
Research and Development, Qatar Research Leadership Program, Qatar Foundation, Doha, Qatar.
Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar.
Douglas Mental Health University Institute, McGill University, Montreal, Canada.
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.


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.

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center