ATLAS: a rationally designed anterograde transsynaptic tracer.

Abstract

Genetically modified rabies virus can map neural circuits retrogradely from genetically determined cells. However, similar tools for anterograde tracing are not available. Here, we describe a method for anterograde transsynaptic tracing from genetically determined neurons based on a rationally designed protein, ATLAS. Expression of ATLAS in neurons causes presynaptic release of a payload composed of an antibody-like protein, AMPA.FingR, which binds to the N terminus of GluA1, and a recombinase. In the synaptic cleft, AMPA.FingR binds to GluA1, causing the payload to be endocytosed into postsynaptic cells and delivered to the nucleus, where it triggers expression of a recombinase-dependent reporter. In mice, ATLAS mediates monosynaptic transneuronal tracing from random or genetically determined cells that is strictly anterograde, synaptic and nontoxic. Moreover, ATLAS-mediated tracing shows activity dependence, suggesting that it can label active circuits underlying specific behaviors. Finally, ATLAS is composed of modular components that can be independently replaced or modified.