Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failure.
Stefan PasslickGhanim UllahChristian HennebergerPublished in: bioRxiv : the preprint server for biology (2024)
Ischemia leads to a severe dysregulation of glutamate homeostasis and excitotoxic cell damage in the brain. Shorter episodes of energy depletion, for instance during peri-infarct depolarizations, can also acutely perturb glutamate signaling. It is less clear if such episodes of metabolic failure also have persistent effects on glutamate signaling and how the relevant mechanisms such as glutamate release and uptake are differentially affected. We modelled acute and transient metabolic failure by using a chemical ischemia protocol and analyzed its effect on glutamatergic synaptic transmission and extracellular glutamate signals by electrophysiology and multiphoton imaging, respectively, in the hippocampus. Our experiments uncover a duration-dependent bidirectional dysregulation of glutamate signaling. Whereas short chemical ischemia induces a lasting potentiation of presynaptic glutamate release and synaptic transmission, longer episodes result in a persistent postsynaptic failure of synaptic transmission. We also observed unexpected differences in the vulnerability of the investigated cellular mechanisms. Axonal action potential firing and glutamate uptake were unexpectedly resilient compared to postsynaptic cells, which overall were most vulnerable to acute and transient metabolic stress. We conclude that even short perturbations of energy supply lead to a lasting potentiation of synaptic glutamate release, which may increase glutamate excitotoxicity well beyond the metabolic incident.
Keyphrases
- cerebral ischemia
- cardiovascular disease
- stem cells
- prefrontal cortex
- coronary artery disease
- spinal cord injury
- mesenchymal stem cells
- single cell
- induced apoptosis
- climate change
- risk assessment
- drug induced
- acute myocardial infarction
- early onset
- left ventricular
- bone marrow
- respiratory failure
- optical coherence tomography
- cell death
- hepatitis b virus
- pi k akt
- mechanical ventilation
- atomic force microscopy