Examining adult hippocampal neurogenesis and cognitive function in Rett syndrome

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Project Summary Rett syndrome (RTT) is a progressive neurological disorder caused by loss-of-function mutations in methyl-CpG- binding protein 2 (MECP2). RTT primarily affects girls and is a frequent cause of X-linked intellectual disability. There are currently no cures for RTT and no available treatments that improve learning and memory function in these patients. Mouse models of RTT mutations recapitulate many aspects of the disorder, including impairments of learning and memory. These animals are critical tools for advancing our understanding of both the basic biology of RTT syndrome and for testing potential treatments. A breakthrough discovery from the Zoghbi and Tang labs found that deep brain stimulation in the hippocampus of RTT mice rescued learning and memory impairments. This stimulation also significantly increased adult hippocampal neurogenesis (AHN), a neural process strongly linked to memory formation, in RTT mice. Whether stimulating AHN alone can improve cognitive function in RTT is unknown. MeCP2 is known to regulate important features of the AHN cascade, such as the proliferation of adult neural stem cells and maturation of adult-born granule neurons. However, the molecular mechanisms disrupting this process in RTT remain unclear. The goal of my project is to address this conceptual gap in our understanding of the how MeCP2 regulates AHN and how AHN contributes to cognitive function in RTT. In my proposal, I focus on two questions: 1) what are the molecular mechanisms disrupting AHN in RTT? 2) Does boosting AHN rescue learning and memory deficits in RTT? I hypothesize that MeCP2 regulates a cell- type-specific transcriptional program important for adult neurogenesis and that enhancing AHN will improve learning and memory performance in RTT animals. In Aim 1, I propose to identify key transcriptional changes during critical stages of AHN by tracking newborn neurons as they develop and using single-nuclei RNA- sequencing to identify the molecular and cellular differences in control vs RTT mice. In Aim 2, I propose to increase AHN via stimulation of the TLX-nuclear receptor, a master regulator of hippocampal neurogenesis, in RTT mice and measure if learning and memory behaviors are rescued. Together, these Aims will help build a comprehensive understanding of how MeCP2 influences AHN and cognitive behaviors in the context of RTT. The ultimate goal of these data will be to identify and develop targeted treatment-based strategies to improve learning and memory function in RTT and potentially other MECP2-related disorders.