Key Findings below. Comments, criticisms, & suggestions welcome. Injection of recombinant AAV into the mouse dentate gyrus kills newborn cells in a dose dependent manner at titers >3E11 gc/ml. Injection of empty AAV capsids show no significant toxicity.
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Tbr2+ cells & recently mitotic neurons up to 1 week old are most susceptible, while Sox2+ cells & neurons >2 weeks old are largely resistant Cells show Caspase3 activation within 12-18 hrs & disappear by 48 hrs, which is not commensurate w/ time course of inflammation.
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Transduction of mouse NPCs by rAAV reproduces dose-dependent toxicity in vitro. Electroporation of synthetic rAAV ITRs into cultured mouse NPCs is sufficient to cause toxicity.
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Injection of AAV retro into CA3 results in efficient retrograde labeling of mature DGCs & permits in vivo 2-photon calcium imaging of dentate activity while leaving adult neurogenesis intact
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What happens in hiPSC-derived NPCs/neurons?
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Haven't tested in hiPSC NPCs yet but hope to shortly. Hirsch et al. described a similar effect in human ES cells so I suspect that if the cells are proliferating they will be susceptible to rAAV toxicity.
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Did you test this with a PHP.B (or eB)? Would you expect the same toxicity, or could the sparsity of infection prevent toxic effects? Compared to a local injection.
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Good question. I suspect that the amount of virus getting into the SGZ would not be enough to see significant toxicity, but don’t know for sure until we try
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Does this only kill cells undergoing neurogenesis? does the infection prevent future neurogenesis in the infected area?
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Cells that are dividing or recently divided are most susceptible. Mature neurons seem resistant. We see no signs of recovery of NG for the duration of our experiments, which is 3 months post injection of rAAV.
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