Nontoxic, double-deletion-mutant rabies viral vectors for retrograde targeting of projection neurons

Nat Neurosci. 2018 Apr;21(4):638-646. doi: 10.1038/s41593-018-0091-7. Epub 2018 Mar 5.

Abstract

Recombinant rabies viral vectors have proven useful for applications including retrograde targeting of projection neurons and monosynaptic tracing, but their cytotoxicity has limited their use to short-term experiments. Here we introduce a new class of double-deletion-mutant rabies viral vectors that left transduced cells alive and healthy indefinitely. Deletion of the viral polymerase gene abolished cytotoxicity and reduced transgene expression to trace levels but left vectors still able to retrogradely infect projection neurons and express recombinases, allowing downstream expression of other transgene products such as fluorophores and calcium indicators. The morphology of retrogradely targeted cells appeared unperturbed at 1 year postinjection. Whole-cell patch-clamp recordings showed no physiological abnormalities at 8 weeks. Longitudinal two-photon structural and functional imaging in vivo, tracking thousands of individual neurons for up to 4 months, showed that transduced neurons did not die but retained stable visual response properties even at the longest time points imaged.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Age Factors
  • Analysis of Variance
  • Animals
  • Cerebral Cortex / physiology*
  • Female
  • Genetic Vectors / genetics*
  • HEK293 Cells
  • Humans
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Neural Pathways / physiology*
  • Neurons / metabolism*
  • Optogenetics
  • Patch-Clamp Techniques
  • Rats
  • Rats, Long-Evans
  • Sequence Deletion / genetics*
  • Thalamus / cytology*
  • Transduction, Genetic

Substances

  • Luminescent Proteins