TY  - JOUR
AU  - Passlick, Stefan
AU  - Ullah, Ghanim
AU  - Henneberger, Christian
TI  - Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failure.
JO  - eLife
VL  - 13
SN  - 2050-084X
CY  - Cambridge
PB  - eLife Sciences Publications
M1  - DZNE-2024-01146
SP  - RP98834
PY  - 2024
AB  - 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 modeled 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 mouse 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 surprisingly resilient compared to postsynaptic cells, which overall were most vulnerable to acute and transient metabolic stress. We conclude that short perturbations of energy supply lead to a lasting potentiation of synaptic glutamate release, which may increase glutamate excitotoxicity well beyond the metabolic incident.
KW  - Animals
KW  - Glutamic Acid: metabolism
KW  - Mice
KW  - Synaptic Transmission
KW  - Hippocampus: metabolism
KW  - Signal Transduction
KW  - Male
KW  - Synapses: metabolism
KW  - Synapses: physiology
KW  - Mice, Inbred C57BL
KW  - glutamate release (Other)
KW  - glutamate uptake (Other)
KW  - ischemia (Other)
KW  - metabolic failure (Other)
KW  - mouse (Other)
KW  - neuroscience (Other)
KW  - stroke (Other)
KW  - synaptic transmission (Other)
KW  - Glutamic Acid (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11407764
C6  - pmid:39287515
DO  - DOI:10.7554/eLife.98834
UR  - https://pub.dzne.de/record/272155
ER  -