Journal Article

AAV ablates neurogenesis in the adult murine hippocampus

Gonçalves, J Tiago, Gage, Fred H, Bloyd, Cooper, Lim, Christina, Mac, Nolan, Saavedra, Christian D, Shtrahman, Matthew, Newberry, Alexander, Novak, Ondrej, Johnston, Stephen, Kim, Stacy, Parylak, Sarah L, Gallina, Iryna

2021

Overview

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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Ablation / adeno-associated virus (AAV) / Adult / adult neurogenesis / Animals / Brain / Calcium imaging / Cell Death / Cell Proliferation / Central Nervous System / dentate gyrus / Dependovirus / Electroporation / Gage, Fred / Gene expression / Gene therapy / Genetic Therapy / Genetic Vectors / Genomes / Granule cells / Hippocampus / Hippocampus - cytology / Hippocampus - physiology / Humans / Inflammation / Injection / Male / Mice / Mice, Inbred C57BL / neural progenitor cell / Neural stem cells / Neural Stem Cells - physiology / Neurogenesis / Neurogenesis - physiology / Neurons / Neurophysiology / Neuroscience / Progenitor cells / Protein expression / Proteins / Stem cell transplantation / Stem cells / Stem Cells and Regenerative Medicine / Toxicity / Vectors (Biology)