Circuit-Specific Targeting of Astrocytes for Genetic Control

Abstract

Astrocytes are integral functional components of brain circuits. They ensheath the connections between neurons to form tripartite synapses. They react to local neuronal activities and release signaling molecules to regulate synaptic transmission. Their dysfunctions impair synaptic functions and are implicated in neuropsychiatric disorders. Increasing evidence indicates that astrocytes are diverse and they have distinct features and functions in different circuits. However, selectively targeting and controlling astrocytes in a circuit-specific manner is technically challenging. Recently we constructed a series of anterograde transneuronal viral vectors based on the yellow fever vaccine YFV-17D. These YFV-17D derivatives express fluorescent proteins almost exclusively in neurons. However, we find that YFV-17D carrying DNA recombinase Cre infect astrocytes associated with the traced neuronal pathways and express Cre to turn on reporter genes. The targeting of astrocytes is at a whole-brain level but specific to the neuronal circuits traced. Therefore, YFV-17D vectors carrying DNA recombinases provide tools for selectively and genetically targeting pathway-specific astrocytes. This new technology will also allow us to reveal the roles of astrocytes in specific neuronal circuits in normal brain functions and diseases.