Single-nucleus profiling reveals a core disease signature and cell type-specific vulnerabilities in early Rett syndrome

Rett syndrome (RTT) is an X-linked neurological disorder caused by <i>MECP2</i> mutations, creating distinct cellular environments in females (mosaic) versus males (nonmosaic). Despite female patients representing most cases, how mosaicism contributes molecularly to RTT pathogenesis, particularly in presymptomatic stages, remains poorly understood. To address this question, we profiled hippocampal transcriptomes of young female and male RTT mice using bulk and single-nucleus RNA sequencing. We identified a core disease signature of consistently dysregulated genes only in MeCP2^- cells across RTT models. Moreover, we uncovered non-cell autonomous effects exclusively in female MeCP2⁺ excitatory neurons, suggesting that these circuits are more vulnerable early in the mosaic RTT environment. The single-nuclei data also revealed an underappreciated MeCP2^- interneuron subtype that had the most transcriptional dysregulation in both male and female RTT hippocampi. Together, these data highlight the different effects of MeCP2 loss on excitatory and inhibitory circuits between the mosaic and nonmosaic environments in early RTT pathogenesis.