Transient Metabolic Failure Leads to Bidirectional Dysregulation of Synaptic Glutamate Signaling

Keskeiset käsitteet

Transient metabolic failure can lead to a duration-dependent bidirectional dysregulation of glutamate release and synaptic transmission, with short durations potentiating glutamate release and longer durations inducing postsynaptic failure.

Tiivistelmä

The study investigated the effects of acute and transient metabolic failure, modeled using a chemical ischemia protocol, on glutamatergic synaptic transmission in the hippocampus. The key findings are:

1. Shorter durations of chemical ischemia (2-3 minutes) led to a persistent potentiation of presynaptic glutamate release and synaptic transmission, while longer durations (4-5 minutes) resulted in a persistent postsynaptic failure of synaptic transmission.

2. The axonal fiber volley, reflecting action potential firing, was relatively resilient and recovered fully even after longer durations of chemical ischemia.

3. Glutamate uptake, primarily mediated by astrocytes, was mostly unaffected by the transient metabolic failure, suggesting a hierarchy of vulnerability with postsynaptic neurons being most susceptible, followed by presynaptic glutamate release, and axonal action potentials and glutamate uptake being the most resilient.

4. The increased glutamate release after shorter durations of metabolic failure was likely due to a broadening of presynaptic action potentials, leading to increased presynaptic Ca2+ influx and vesicular glutamate release, rather than a reduction in glutamate uptake.

These findings reveal that even short perturbations of energy supply can lead to a lasting potentiation of synaptic glutamate release, which may increase glutamate excitotoxicity beyond the initial metabolic incident, such as during peri-infarct depolarizations in ischemic stroke.

Tilastot

Shorter durations of chemical ischemia (2-3 minutes) led to a persistent potentiation of the postsynaptic response, while longer durations (4-5 minutes) resulted in a persistent suppression.
The axonal fiber volley amplitude was not different between control and chemical ischemia recordings, indicating resilience of action potential firing.
The decay time constant of the iGluSnFR fluorescence transients, a measure of glutamate clearance, was not affected by chemical ischemia.

Lainaukset

"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 an unexpected hierarchy of vulnerability of the involved mechanisms and cell types. 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."

Tärkeimmät oivallukset

Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failure

by Passlick,S.,... klo www.biorxiv.org 04-12-2024

https://www.biorxiv.org/content/10.1101/2024.04.11.588988v1

Syvällisempiä Kysymyksiä

How might the bidirectional changes in glutamate signaling observed in this study impact neuronal excitability and the progression of tissue damage in the peri-infarct zone during ischemic stroke?

The bidirectional changes in glutamate signaling observed in this study could have significant implications for neuronal excitability and the progression of tissue damage in the peri-infarct zone during ischemic stroke. The persistent potentiation of glutamate release after shorter durations of metabolic failure could lead to an increase in excitatory neurotransmission in the affected area. This could result in heightened neuronal excitability, making the neurons more prone to firing action potentials and transmitting signals. As a consequence, this increased excitability could contribute to the spread of excitotoxicity, where excessive activation of glutamate receptors leads to neuronal damage and cell death.
On the other hand, the postsynaptic failure of synaptic transmission observed after longer durations of metabolic failure could have a dampening effect on neuronal activity in the peri-infarct zone. This could potentially protect the neurons from excessive excitatory input and reduce the risk of excitotoxicity. However, the lack of synaptic transmission could also lead to functional deficits and impairments in neural communication in the affected area.
Overall, the bidirectional changes in glutamate signaling could create a complex interplay between excitatory and inhibitory processes in the peri-infarct zone. This dynamic balance of excitation and inhibition could influence the extent of tissue damage, the spread of neuronal dysfunction, and the overall outcome of ischemic stroke in the affected brain region.

How might the bidirectional changes in glutamate signaling observed in this study impact neuronal excitability and the progression of tissue damage in the peri-infarct zone during ischemic stroke?

The bidirectional changes in glutamate signaling observed in this study could have significant implications for neuronal excitability and the progression of tissue damage in the peri-infarct zone during ischemic stroke. The persistent potentiation of glutamate release after shorter durations of metabolic failure could lead to an increase in excitatory neurotransmission in the affected area. This could result in heightened neuronal excitability, making the neurons more prone to firing action potentials and transmitting signals. As a consequence, this increased excitability could contribute to the spread of excitotoxicity, where excessive activation of glutamate receptors leads to neuronal damage and cell death.
On the other hand, the postsynaptic failure of synaptic transmission observed after longer durations of metabolic failure could have a dampening effect on neuronal activity in the peri-infarct zone. This could potentially protect the neurons from excessive excitatory input and reduce the risk of excitotoxicity. However, the lack of synaptic transmission could also lead to functional deficits and impairments in neural communication in the affected area.
Overall, the bidirectional changes in glutamate signaling could create a complex interplay between excitatory and inhibitory processes in the peri-infarct zone. This dynamic balance of excitation and inhibition could influence the extent of tissue damage, the spread of neuronal dysfunction, and the overall outcome of ischemic stroke in the affected brain region.

How might the bidirectional changes in glutamate signaling observed in this study impact neuronal excitability and the progression of tissue damage in the peri-infarct zone during ischemic stroke?

The bidirectional changes in glutamate signaling observed in this study could have significant implications for neuronal excitability and the progression of tissue damage in the peri-infarct zone during ischemic stroke. The persistent potentiation of glutamate release after shorter durations of metabolic failure could lead to an increase in excitatory neurotransmission in the affected area. This could result in heightened neuronal excitability, making the neurons more prone to firing action potentials and transmitting signals. As a consequence, this increased excitability could contribute to the spread of excitotoxicity, where excessive activation of glutamate receptors leads to neuronal damage and cell death.
On the other hand, the postsynaptic failure of synaptic transmission observed after longer durations of metabolic failure could have a dampening effect on neuronal activity in the peri-infarct zone. This could potentially protect the neurons from excessive excitatory input and reduce the risk of excitotoxicity. However, the lack of synaptic transmission could also lead to functional deficits and impairments in neural communication in the affected area.
Overall, the bidirectional changes in glutamate signaling could create a complex interplay between excitatory and inhibitory processes in the peri-infarct zone. This dynamic balance of excitation and inhibition could influence the extent of tissue damage, the spread of neuronal dysfunction, and the overall outcome of ischemic stroke in the affected brain region.