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

Douglas Vormstein-Schneider, Jessica D. Lin, Kenneth A. Pelkey, Ramesh Chittajallu, Baolin Guo, Mario A. Arias-Garcia, Kathryn Allaway, Sofia Sakopoulos, Gates Schneider, Olivia Stevenson, Josselyn Vergara, Jitendra Sharma, Qiangge Zhang, Tom P. Franken, Jared Smith, Leena A. Ibrahim, Kevin J. M astro, Ehsan Sabri, Shuhan Huang, Emilia FavuzziTimothy Burbridge, Qing Xu, Lihua Guo, Ian Vogel, Vanessa Sanchez, Giuseppe A. Saldi, Bram L. Gorissen, Xiaoqing Yuan, Kareem A. Zaghloul, Orrin Devinsky, Bernardo L. Sabatini, Renata Batista-Brito, John Reynolds, Guoping Feng, Zhanyan Fu, Chris J. McBain, Gord Fishell, Jordane Dimidschstein

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1629-1636
Number of pages8
JournalNature Neuroscience
Volume23
Issue number12
DOIs
StatePublished - Dec 2020

ASJC Scopus subject areas

  • Neuroscience(all)

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