RT Journal Article
SR Electronic
T1 AAV Ablates Neurogenesis in the Adult Murine Hippocampus
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.18.911362
DO 10.1101/2020.01.18.911362
A1 ST Johnston
A1 SL Parylak
A1 S Kim
A1 N Mac
A1 CK Lim
A1 IS Gallina
A1 CW Bloyd
A1 A Newberry
A1 CD Saavedra
A1 O Novák
A1 JT Gonçalves
A1 FH Gage
A1 M Shtrahman
YR 2020
UL http://biorxiv.org/content/early/2020/01/19/2020.01.18.911362.abstract
AB 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.