FOR 2795:  Synapses under stress: Early events induced by metabolic failure at glutamatergic synapses

• Subject Area: Biology ; Medicine
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 394431587

The brain is one of the major energy consumers of the human body. Under normal conditions, oxidative phosphorylation by mitochondria is responsible for producing most of the ATP in the mammalian brain. However, cerebral ischemia, a pathological condition in which blood flow to the brain is too low to meet its high metabolic demands, rapidly reduces cellular ATP levels. This can result in either reversible loss of brain function or irreversible damage, depending on the remaining perfusion level and metabolic demand of the affected brain region. Considerable efforts have been made to elucidate the late processes causing cell damage and death, but the sequence of early events following decreased cellular ATP availability and the temporal progression of pre- versus postsynaptic changes remain largely unexplored. As these synaptic changes are among the earliest and most upstream events in the ischemic cascade, a better understanding of the causes of metabolic stress in synapses during ischemia is highly relevant for translation into clinical applications. Research Unit (RU) 2795 "Synapses under stress: Early events induced by metabolic failure at glutamatergic synapses" closes this gap by analysing the major compartments of glutamatergic synapses: pre- and postsynaptic neuronal compartments, perisynaptic astrocytes and the extracellular space. It covers all major determinants of synaptic function, including adaptation mechanisms and the reversibility of adverse effects, and analyses their consequences for synaptic function. We study crosstalk between the different compartments, with a special focus on key organelles (such as synaptic vesicles, mitochondria, and lysosomes), in order to obtain a comprehensive understanding of the complex (intra-) cellular interactions that occur at synapses. In addition to the mouse cortex, we study preparations derived from human induced pluripotent stem cells (iPSCs) as new model systems to promote the translation of our findings to the context of the human brain. The use of novel cellular imaging approaches, modern molecular biology tools and new model systems, together with mathematical simulations, allows the study of the energy dependence of synapses and the acute consequences of restricted energy supply on synaptic function at unprecedented spatial and temporal resolution. We expect our research programme to lead to a thorough understanding of the immediate responses of the tripartite synapse to transient energy shortage and their functional consequences and of the potential reversibility of the induced effects. This will generate a new, integrative view of basic pathomechanisms of metabolic failure, which is urgently needed to develop better therapeutic strategies to combat stroke-induced brain damage.

• DFG Programme: Research Units
• International Connection: Netherlands

Projects

• Causes and consequences of dysregulated extracellular glutamate signalling after metabolic stress (Applicant Henneberger, Christian )
• Chloride homeostasis in neuronal compartments under acute metabolic stress (Applicant Fahlke, Christoph )
• Coordination Funds (Applicant Rose, Christine R. )
• Functional, structural and metabolic consequences of ionic dysbalance in stroke (Applicant Petzold, Gabor )
• Impact and adaptation of glutamate receptor signaling in metabolic stress conditions (Applicant Reiner, Andreas )
• Life cycle of AMPA receptors under acute metabolic stress (Applicant Erlenhardt, Nadine )
• Mechanisms of presynaptic dysfunction under acute metabolic stress (Applicant Klingauf, Jürgen )
• Mitochondrial remodeling in human neurons, astrocytes, and brain organoids under metabolic failure (Applicants Anand, Ph.D., Ruchika ;  Prigione, Ph.D., Alessandro )
• New pathways driving sodium dysregulation under acute metabolic stress (Applicant Rose, Christine R. )
• The tripartite synapse during metabolic stress (Applicant Rose, Christine R. )

• Spokesperson: Professorin Dr. Christine R. Rose