AAV ablates neurogenesis in the adult murine hippocampus.

Autor:	Johnston S; Neurosciences Graduate Program, University of California, San Diego, La Jolla, United States.; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States., Parylak SL; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States., Kim S; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States.; Department of Neurosciences, University of California, San Diego, La Jolla, United States., Mac N; Department of Biology, University of California, San Diego, La Jolla, United States., Lim C; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States., Gallina I; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States., Bloyd C; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States., Newberry A; Department of Physics, University of California, San Diego, La Jolla, United States., Saavedra CD; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States., Novak O; Laboratory of Experimental Epileptology, Department of Physiology, Second Faculty of Medicine, Charles University, Prague, United Kingdom., Gonçalves JT; Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, United States.; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, United States., Gage FH; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States., Shtrahman M; Department of Neurosciences, University of California, San Diego, La Jolla, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Jul 14; Vol. 10. Date of Electronic Publication: 2021 Jul 14.
DOI:	10.7554/eLife.59291
Abstrakt:	Recombinant adeno-associated virus (rAAV) has been widely used as a viral vector across mammalian biology and has been shown to be safe and effective in human gene therapy. We demonstrate that neural progenitor cells (NPCs) and immature dentate granule cells (DGCs) within the adult murine hippocampus are particularly sensitive to rAAV-induced cell death. Cell loss is dose dependent and nearly complete at experimentally relevant viral titers. rAAV-induced cell death is rapid and persistent, with loss of BrdU-labeled cells within 18 hr post-injection and no evidence of recovery of adult neurogenesis at 3 months post-injection. The remaining mature DGCs appear hyperactive 4 weeks post-injection based on immediate early gene expression, consistent with previous studies investigating the effects of attenuating adult neurogenesis. In vitro application of AAV or electroporation of AAV2 inverted terminal repeats (ITRs) is sufficient to induce cell death. Efficient transduction of the dentategyrus (DG)- without ablating adult neurogenesis- can be achieved by injection of rAAV2-retro serotyped virus into CA3. rAAV2-retro results in efficient retrograde labeling of mature DGCs and permits in vivo two-photon calcium imaging of dentate activity while leaving adult neurogenesis intact. These findings expand on recent reports implicating rAAV-linked toxicity in stem cells and other cell types and suggest that future work using rAAV as an experimental tool in the DG and as a gene therapy for diseases of the central nervous system should be carefully evaluated. Competing Interests: SJ, SP, SK, NM, CL, IG, CB, AN, CS, ON, JG, FG, MS No competing interests declared (© 2021, Johnston et al.)
Databáze:	MEDLINE
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