Abstract
Adult neurogenesis exists in two brain regions: the subventricular zone (SVZ) and the hippocampal dentate gyrus. In schizophrenia, hippocampal neurogenesis has been widely characterized, however no evidence exists for whether SVZ neurogenesis might be involved in the disease. This is particularly interesting since antipsychotic drugs were already shown to increase SVZ neurogenesis in rats [1, 2]. Here, I have investigated adult neurogenesis in three mouse models of schizophrenia: transgenic mice overexpressing neuregulin-1 type 1 (NRG1type1-tg); Snap-25 mutant (SNAP25+/-) mice and dysbindin-1 mutant or Sandy (Sdy-/-) mice. Using immunohistochemistry, I found no quantitative change in the number of proliferative cells that were positive for phosophohistone (PHi3) in the SVZ, rostral migratory stream (RMS) and hippocampus in both the NRG1type1-tg and SNAP25+/- mice. Similarly, I found no significant change in the surface area of migrating neuroblasts (doublecortin, Dcx+ cells) in the RMS of NRG1type1-tg and SNAP25+/- mice. The third model, Sdy-/- mice, were systemically injected with either saline or a viral mimic, polyI:C, from postnatal day 5 (P5) to P9 and this model represents gene vs. environment interactions in schizophrenia. Interestingly, I found a significant reduction in the number of proliferative (PHi3+) cells in the medial and subcallosal SVZ of Sdy-/- mice after inflammation. Also, I have found a decrease in the surface area of migratory (Dcx+) cells in the RMS of Sdy-/- (+polyI:C). Furthermore, I sought to find whether neonatal stress causes morphological changes in astroyctosis (i.e. GFAP) and microglia activation (i.e. Iba1) in the SVZ of Sdy-/- mice but found no apparent differences in comparison to wild-type (WT) littermates. Our collaborators from Prof. Lalit Srivastava's laboratory (McGill University) have shown that these observations in Sdy-/- mice (+polyI:C) were correlated with behavioural abnormalities, such as prepulse inhibition (PPI), reduced locomotor activity and object-recognition deficit although the latter was not statistically significant. In conclusion, I have shown here that a combination of both neonatal inflammation and mutation in a gene relevant to schizophrenia was important for triggering long-term effects in SVZ neurogenesis that was also correlated with behavioural deficits. Future studies will further examine SVZ neurogenesis in postnatal Sandy mice and will also look at brain integrity and cytokine infiltration in both postnatal and adult Sandy mice following neonatal inflammation. Functional studies will determine whether knocking-down toll-like receptor-3 (TLR3), which is the receptor for polyI:C, might rescue SVZ neurogenesis in postnatal Sandy mice after inflammation. 1. Kippin, T.E., S. Kapur, and D. van der Kooy, Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs. J Neurosci, 2005. 25(24): p. 5815-23. 2. Wakade, C.G., et al., Atypical neuroleptics stimulate neurogenesis in adult rat brain. J Neurosci Res, 2002. 69(1): p. 72-9.
Original language | English |
---|---|
Title of host publication | Qatar Foundation Annual Research Forum Volume 2013 Issue 1 |
Volume | 2013 |
Edition | 1 |
Publication status | Published - Nov 2013 |
Externally published | Yes |