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AAV Ablates Neurogenesis in the Adult Murine Hippocampus

ST Johnston, SL Parylak, S Kim, N Mac, CK Lim, IS Gallina, CW Bloyd, A Newberry, CD Saavedra, O Novák, JT Gonçalves, FH Gage, M Shtrahman
doi: https://doi.org/10.1101/2020.01.18.911362
ST Johnston
Neurosciences Graduate Program, University of California San Diego – La Jolla, CA USALaboratory of Genetics, Salk Institute for Biological Studies – La Jolla, CA USA
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SL Parylak
Laboratory of Genetics, Salk Institute for Biological Studies – La Jolla, CA USA
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S Kim
Laboratory of Genetics, Salk Institute for Biological Studies – La Jolla, CA USA
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N Mac
Department of Biology, University of California San Diego – La Jolla, CA USA
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CK Lim
Laboratory of Genetics, Salk Institute for Biological Studies – La Jolla, CA USA
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IS Gallina
Laboratory of Genetics, Salk Institute for Biological Studies – La Jolla, CA USA
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CW Bloyd
School of Medicine, University of California San Francisco – La Jolla, CA USA
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A Newberry
Department of Physics, University of California San Diego – La Jolla, CA USA
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CD Saavedra
Laboratory of Genetics, Salk Institute for Biological Studies – La Jolla, CA USA
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O Novák
Laboratory of Experimental Epileptology, Department of Physiology, Second Faculty of Medicine, Charles University – Prague, CZ
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JT Gonçalves
Department of Neuroscience, Albert Einstein College of Medicine – Bronx, NY USA
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FH Gage
Laboratory of Genetics, Salk Institute for Biological Studies – La Jolla, CA USA
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  • For correspondence: gage@salk.edu mshtrahman@ucsd.edu
M Shtrahman
Department of Neurosciences, University of California San Diego – La Jolla, CA USA
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  • For correspondence: gage@salk.edu mshtrahman@ucsd.edu
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ABSTRACT

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 hours 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 dentate gyrus (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 2-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 (CNS) should be carefully evaluated.

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Posted January 19, 2020.
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AAV Ablates Neurogenesis in the Adult Murine Hippocampus
ST Johnston, SL Parylak, S Kim, N Mac, CK Lim, IS Gallina, CW Bloyd, A Newberry, CD Saavedra, O Novák, JT Gonçalves, FH Gage, M Shtrahman
bioRxiv 2020.01.18.911362; doi: https://doi.org/10.1101/2020.01.18.911362
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AAV Ablates Neurogenesis in the Adult Murine Hippocampus
ST Johnston, SL Parylak, S Kim, N Mac, CK Lim, IS Gallina, CW Bloyd, A Newberry, CD Saavedra, O Novák, JT Gonçalves, FH Gage, M Shtrahman
bioRxiv 2020.01.18.911362; doi: https://doi.org/10.1101/2020.01.18.911362

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