Active intermixing of indirect and direct neurons builds the striatal mosaic

Abstract

The striatum controls behaviors via the activity of direct and indirect pathway projection neurons (dSPN and iSPN) that are intermingled in all compartments. While such mosaic ensures the balanced activity of the two pathways, how it emerges remains largely unknown. Here, we show that both SPN populations are specified embryonically and progressively intermix through multidirectional iSPN migration. Using conditional mutants of the dSPN-specific transcription factor Ebf1, we found that inactivating this gene impaired selective dSPN properties, including axon pathfinding, whereas molecular and functional features of iSPN were preserved. Remarkably, Ebf1 mutation disrupted iSPN/dSPN intermixing, resulting in an uneven distribution. Such architectural defect was selective of the matrix compartment, revealing that intermixing is a parallel process to compartment formation. Our study reveals that, while iSPN/dSPN specification is largely independent, their intermingling emerges from an active migration of iSPN, thereby providing a novel framework for the building of striatal architecture.