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Functional Correlates of Adult Hippocampal Neurogenesis & Sensitivity of Hippocampal Neural Progenitor Cells to rAAV-induced Cell-death

  • Author(s): Johnston, Stephen Thomas
  • Advisor(s): Gage, Fred H
  • et al.
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Abstract

The elegantly delineated anatomy of the hippocampus has long served as a substrate for theories of memory formation and recall. Principally, the Dentate Gyrus (DG) has been proposed to be important in the encoding and formation of new memories through a process known as pattern separation, while downstream CA3 has been proposed to play a role in memory recall through a process known as pattern completion. In vivo optical methods have provided access to study computation within the DG and the activity of dentate granule cells (DGCs) has been associated with hippocampus-dependent behavioral pattern separation and pattern completion. Increasing evidence supports the idea that a rare population of immature adult-born DGCs (abDGCs) 4-6 weeks of age support pattern-separation in the DG by enhancing feedback inhibition onto mature DGCs. These studies rely almost exclusively on recominant Adeno-associated Virus (rAAV) for transgene delivery, however the toxic effects of rAAV on this circuit were not been assessed.

Herein, we demonstrate that neural progenitor cells (NPCs) and immature 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 when assessed 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. This rAAV-induced toxicity is intrinsic to the rAAV viral vector. Finally, efficient transduction of the DG is achieved by injection of rAAV2-retro serotyped virus into CA3 and permits in vivo 2-photon calcium imaging of dentate activity while leaving adult neurogenesis intact. Using this method we demonstrate functional changes to mature DGC activity 2-weeks following abDGC ablation using rAAV. These findings expand on recent reports implicating rAAV linked toxicity in stem cells and other cell types and suggests future work using rAAV in the DG should be carefully evaluated.

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This item is under embargo until June 26, 2020.