Viral manipulation of functionally distinct interneurons in mice, non-human primates and humans

Nat Neurosci. 2020 Dec;23(12):1629-1636. doi: 10.1038/s41593-020-0692-9. Epub 2020 Aug 17.


Recent success in identifying gene-regulatory elements in the context of recombinant adeno-associated virus vectors has enabled cell-type-restricted gene expression. However, within the cerebral cortex these tools are largely limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple new enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we discovered enhancers selective for parvalbumin (PV) and vasoactive intestinal peptide-expressing interneurons. Demonstrating the functional utility of these elements, we show that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across vertebrate species, including humans. Finally, we demonstrate that our selection method is generalizable and characterizes additional PV-specific enhancers with exquisite specificity within distinct brain regions. Altogether, these viral tools can be used for cell-type-specific circuit manipulation and hold considerable promise for use in therapeutic interventions.

Publication types

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

MeSH terms

  • Animals
  • Callithrix
  • Cerebral Cortex / cytology
  • Dependovirus / genetics*
  • Female
  • Genetic Vectors / genetics*
  • Humans
  • Interneurons / physiology*
  • Macaca mulatta
  • Mice
  • Mice, Inbred C57BL
  • NAV1.1 Voltage-Gated Sodium Channel / genetics
  • Neurons
  • Parvalbumins / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Species Specificity
  • Vasoactive Intestinal Peptide / physiology


  • NAV1.1 Voltage-Gated Sodium Channel
  • Parvalbumins
  • Scn1a protein, mouse
  • Vasoactive Intestinal Peptide