Excitation/inhibition dysbalance in murine and human models of MeCP2 deficiency and Rett syndrome

• Applicant: Professor Dr. Christian Rosenmund
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437833719

Rett syndrome (RTT) is a progressive childhood neurodevelopmental disorder, resulting predominantly from loss-of-function mutations in the X-linked gene encoding the transcriptional regulator, methyl-CpG binding protein 2 (MeCP2). Loss of murine MeCP2 results in changes in both excitatory and inhibitory neuron function, indicate that MeCP2 plays a pivotal role in maintaining precise excitation-inhibition balance in neural circuits. Our general objective is to elucidate the cellular dysfunction and interaction of these neurons in RTT with a focus on BDNF, which is a central mediator of neuronal function and dysfunction in Rett syndrome. We will utilized single cell sequencing technologies to directly correlate single cell transcriptomes with disturbances in cellular morphology and function. In addition, we plan to port studies from mouse models to human RTT neurons using a patient-derived stem cell-induced neuron model recently established in our lab. These approaches will significantly enhance our understanding of the pathomechanism of RTT at the level of cells and cellular networks, and allow us to explore putative therapeutic targets and develop more rapid bench-to-patient approaches in RTT.

• DFG Programme: Research Grants