Excitation/inhibition dysbalance in murine and human models of MeCP2 deficiency and Rett syndrome
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Rett syndrome (RTT) is a progressive childhood neurodevelopmental disorder, resulting predominantly from loss-of-function mutations in the X-linked gene MECP2 encoding the transcriptional regulator, methyl-CpG binding protein 2 (MeCP2). MeCP2 regulates a wide range of downstream target genes by both transcriptional activation and repression. RTT almost exclusively affects females with an incidence rate of approximately 1 in 10,000, and is characterized by an initial period of apparently normal development between 6 and 18 months followed by developmental regression. Rett patients display classical signs of impaired excitation-inhibition balance within neural circuits, leading to epilepsy, autism and dysregulation of respiratory rhythms. We have identified in the past important roles of MeCP2 protein levels in regulating synaptic strength both for glutamatergic and GABAergic neurons, and identified the role of BDNF as a key regulator for MeCP2 dependent regulation in glutamatergic neurons. In this project we explored several unclear aspects of synaptic interactions between glutamatergic and GABAergic neurons, and moved the analysis of these interaction in the human neuron space and included single cell sequencing approaches to better understand the alteration in synaptic function in both glutamatergic and GABAergic neurons.
Publications
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Cannabinoid receptor activation acutely increases synaptic vesicle numbers by activating synapsins in human synapses. Molecular Psychiatry, 26(11), 6253-6268.
Patzke, Christopher; Dai, Jinye; Brockmann, Marisa M.; Sun, Zijun; Fenske, Pascal; Rosenmund, Christian & Südhof, Thomas C.
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Impaired inhibitory GABAergic synaptic transmission and transcription studied in single neurons by Patch-seq in Huntington’s disease. Proceedings of the National Academy of Sciences, 118(19).
Paraskevopoulou, Foteini; Parvizi, Poorya; Senger, Gökçe; Tuncbag, Nurcan; Rosenmund, Christian & Yildirim, Ferah
