Combining neonatal stress with schizophrenia susceptibility gene, dysbindin-1, is required for phenotypic changes in adulthood.
Bibliographic record
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; both teacher heads agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".