Reference:
Michael Müller
Abstract:
Rett patients and mouse models of Rett syndrome, i.e. mice carrying mutations in the gene coding for the transcriptional regulator MeCP2, suffer from highly irregular breathing with temporary arrest of breathing, which gives rise to repeated episodes of reduced systemic oxygen supply (hypoxia). Yet, instead of desensitization or neuronal adaptation to such intermittent hypoxia, we rather found an increased hypoxia susceptibility of the hippocampus and brainstem of MeCP2-deficient mice. In hippocampal pyramidal neurons we confirmed a dysfunction of K+ channels and a disturbed regulation of intracellular Ca2+ levels. Also, the function and metabolism of mitochondria – the cellular “power plants” – is affected. Acting as multi-purpose cell organelles, mitochondria are the most important supplier of cellular energy, contribute to cellular Ca2+ regulation, constitute a major source of reactive oxygen species (ROS) and may thus critically modulate neuronal activity and excitability in various ways. In patients and mice MeCP2-deficiency is well known to affect mitochondrial structure and function, and there are clear signs of increased ROS-mediated oxidative damage of cellular components. Therefore, we are now aiming to decipher the interplay of mitochondrial dysfunction, the associated ROS-mediated redox imbalance and cellular Ca2+ regulation and its resulting impact on neuronal function in MeCP2-deficient mouse hippocampus. Using high-resolution microscopy and novel optical probes will allow to rate mitochondrial function and correlate it with cytosolic and mitochondrial ROS levels. Quantitative optical recordings of intracellular Ca2+ levels combined with detailed electrophysiological analyses will address the efficiency of cellular Ca2+ regulation under various ROS-levels in correlation with neuronal activity and plasticity. These studies will be complemented by biochemical assays rating the efficiency of mitochondrial metabolism under normal and limited oxygen supply. We consider a detailed molecular understanding of this fascinating neurochemical interplay and its impact on the function of complex neuronal networks as a crucial contribution to the molecular understanding of the neurobiology of Rett syndrome and the development of novel successful pharmacotherapy. Following this concept we will clarify whether modulating Ca2+ homeostasis and redox balance is capable of restoring neuronal plasticity. – See more at: http://www.rettsyndrome.org/research-programs/funded-projects/research-awardees-2011#sthash.dd1Ofrop.dpuf
PROJECT DETAILS
beginning: 2011.
end: 2013.
Country of research: Germany
Counry of funding source: United States
Funding organization: International Rett Syndrome Foundation (Regular Researh Grant)
Financing: PRIVATE FUNDERS – 146 872 €