Effect of Mecp2 Mutation on Cortical Projections Revealed by Correlated Single-Cell Transcriptomics and Projectomics

ABSTRACT

Rett Syndrome is caused by mutations in Mecp2, which result in a constellation of language, cognitive, motor, and autonomic deficits later in life. Although changes in long-range neuronal connectivity likely underlie the behavioral defects in Rett syndrome, it is unclear how long-range axonal projections are disrupted. Here we develop and apply high-throughput single-cell techniques to identify cell type-specific changes in projections in Mecp2 animals. We identified two subtypes of cortical projection neurons with potential changes in long-range projections, including the corticothalamic neurons and L6b neurons. Our results provide candidate cell types for future in depth studies on the long-range circuitry changes associated with Mecp2 mutation. Furthermore, our approach is generally applicable to other brain areas and disease models to reveal cell type-specific changes in projections that are difficult to detect using conventional methods.