Enhancer-Driven Gene Expression (EDGE) Enables the Generation of Viral Vectors Specific to Neuronal Subtypes

Highlights

• rAAVs with enhancers unique to a brain region specify cell types of that brain region

• This requires viral constructs optimized to express only with enhancers

• One rAAV distinguishes distinct subtypes of excitatory neurons in a cortical layer

• The same specificity is seen in wild-type animals of at least two species

Summary

Although a variety of remarkable molecular tools for studying neural circuits have recently been developed, the ability to deploy them in particular neuronal subtypes is limited by the fact that native promoters are almost never specific enough. We recently showed that one can generate transgenic mice with anatomical specificity surpassing that of native promoters by combining enhancers uniquely active in particular brain regions with a heterologous minimal promoter, an approach we call EDGE (Enhancer-Driven Gene Expression). Here we extend this strategy to the generation of viral (rAAV) vectors, showing that some EDGE rAAVs can recapitulate the specificity of the corresponding transgenic lines in wild-type animals, even of another species. This approach thus holds the promise of enabling circuit-specific manipulations in wild-type animals, not only enhancing our understanding of brain function, but perhaps one day even providing novel therapeutic avenues to approach disorders of the brain.