Project Details
Projekt
Impact and adaptation of glutamate receptor signaling in metabolic stress conditions
Applicant
Professor Dr. Andreas Reiner
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 394431587
Ionotropic glutamate receptors (iGluRs) are thought to play a key role for perpetuating metabolic stress. Energy depletion in the central nervous system causes rapid depolarization, which leads to an increased release of the neurotransmitter glutamate and hinders its uptake by glial cells. The resulting glutamate spill may over-excite iGluRs, thus causing further depolarization and spreading excitotoxicity. Several key steps in this cascade deserve further attention: In this project we aim to investigate how different iGluR subtypes are affected during acute ischemic episodes, how they contribute to the ischemic insult, and how signaling through synaptic iGluR adapts.Recently developed optical sensors show relevant and prolonged increases of the extracellular glutamate concentration even during moderate chemical ischemia in cortical organotypic slice cultures. We will proceed by addressing whether this causes over-activation or desensitization of AMPA and kainate receptors. For this we will use photo-switchable iGluRs in combination with electrophysiology, which allows us to probe the activation state of representative iGluRs in real time. NMDA receptor over-activation, which readily occurs at even low glutamate concentrations, is known to be especially damaging. Here, we seek to dissect how specific NMDA receptor subunits affect other channel proteins that have recently been linked to NMDA receptor-mediated excitotoxicity. Last, given the severe depolarization and massive calcium loading during ischemia, we will investigate adaptations of synaptic receptor populations by analyzing changes of AMPA and NMDA receptor currents. Overall, this project will provide further insight into the role of iGluR signaling during episodes of metabolic stress and recovery. A detailed understanding of these pathomechanisms may also point to new options for pharmacological intervention. The project is part of the Research Unit "Early events induced by metabolic failure at glutamatergic synapses".
DFG Programme
Research Units
