Project Details
Projekt
Causes and consequences of dysregulated extracellular glutamate signalling after metabolic stress
Applicant
Professor Dr. Christian Henneberger
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 394431587
Impairment or failure of extracellular glutamate homeostasis is a central step in the pathophysiology of brain ischemia because it leads to excessive cellular excitation and thereby to excitotoxicity. In the context of stroke, it is believed for instance that the accumulation and increased escape of glutamate into extrasynaptic space and its excitotoxic action through extrasynaptic N-methyl-D-aspartate receptors is a major mechanism underlying cell damage and death. However, the sequence of events and specific mechanisms that lead to perturbed glutamate signalling, the relationship between duration and severity of acute metabolic stress, the activated mechanisms and the functional changes of extracellular glutamate dynamics remain to be fully uncovered. In the past two years of the 1st funding period, we have discovered that acute metabolic stress has two qualitatively distinct outcomes depending on its severity. Whereas severe metabolic stress leads a transient surge of extracellular glutamate and a lasting suppression of postsynaptic field responses, moderate metabolic stress does not and instead triggers a persistent increase of synaptically driven extracellular glutamate transients and of synaptic transmission. We propose to establish the underlying mechanisms and their functional implications. There will be three main themes: 1) cellular and subcellular specificity of dysregulated extracellular glutamate signalling, 2) mechanisms underlying the dysregulation of glutamate signalling, and 3) interdependence of glutamate dysregulation and ischemic long-term potentiation in vitro and in vivo. By exploring these topics, we will reveal new causes and consequences of altered extracellular glutamate signalling during and after acute metabolic stress and in ischemia.
DFG Programme
Research Units
