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Title: Novel functions of schizophrenia-related dysbindin-1 in the subventricular zone
Author: Al-Shammari, Abeer
ISNI:       0000 0004 6495 8517
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Schizophrenia is a neurodevelopmental disorder that has widely been associated with environmental and genetic risk factors. However, direct functional interactions between the two risk factors remain unclear. Therefore, I sought to address how the schizophrenia-related dysbindin-1 may functionally mediate polyI:C-induced inflammation and the importance of this interaction on neurodevelopment in the subventricular zone (SVZ). I focused on the SVZ niche since it lies at the interface between systemic inflammation and neurogenic homeostasis. The interacting effects of dysbindin-1 and polyI:C on microglia, cytokine secretion and leukocyte permeability into the SVZ were also characterised. Multiple systemic polyI:C injections during early postnatal development in dysbindin-1 mutant (Sandy, Sdy) mice resulted in reduced adult SVZ proliferation and reduced neuroblast populations in the rostral migratory stream (RMS). This was also correlated with reduced prepulse inhibition, decreased locomotor activity, object recognition deficit as well as long-term reduction in body weights in adulthood. Postnatal SVZ proliferation was also reduced in Sdy mice given postnatal polyI:C indicating a neurodevelopmental origin of these abnormalities in adulthood. In contrast to these results, adult SVZ proliferation as well as proliferation and neuroblast populations in the RMS were unaffected in transgenic mice overexpressing neuregulin-1 type I (NRG1typeI-tg) and Snap25 mutant (SNAP25+/-) mice that were not immune challenged. I analyzed the expression of toll-like receptor 3 (Tlr3), RelA and Sp1 which are important in the innate immune response and cell proliferation in order to determine how dysbindin-1 and polyI:C mediate their expression. PolyI:C administration to WT SVZ in vivo and in vitro induced the expression of its receptor Tlr3 and the downstream transcription factors RelA and Sp1 indicating a normal inflammatory response. Unexpectedly, in vitro and in vivo polyI:C administration also increased dysbindin-1 expression in WT SVZ, suggesting an inflammatory role for dysbindin-1. This was confirmed in Sdy mice that showed inhibited Tlr3, RelA and Sp1 expression in the SVZ following polyI:C administration both in vivo and in vitro. Furthermore, overexpression of dysbindin-1 (Dtnbp1) gene rescued Tlr3 and RelA expression in vitro in neurospheres prepared from Sdy mice. Supporting the notion that dysbindin-1 regulates immune function, SVZ microglial density was higher in Sdy than in WT mice. Also, more leukocytes were found in the postnatal SVZ of Sdy mice following systemic polyI:C injections than in WT mice given saline. Finally, differential cytokine secretion was detected in Sdy neurospheres in comparison to WT neurospheres under baseline and inflammatory conditions. Taken together, I report novel functions of the schizophrenia-relevant dysbinidin-1 in regulating microglial density in the SVZ, and provide evidence for a direct interaction between dysbindin-1 and polyI:C-induced inflammation that is required for maintaining SVZ proliferation, mediating cytokine secretion and restricting leukocyte infiltration into the SVZ. This work provides a novel mechanistic framework for further studying the relationship between genes and environment in the context of schizophrenia.
Supervisor: Szele, Francis Sponsor: Qatar Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available