Excitotoxicity Flashcards
What is glutamate derived from?
alpha-ketoglutarate
Where does aspartate function as a NT?
Visual cortex
Pyramidal cells
What does NDMA channel allow passage of?
What can activate it?
Ca++
Glutamate, aspartate, etc.
What does NDMA require in addition to an EAA?
Glycine
What 2 things can block the NDMA?
Mg++
PCP
What unique thing does Mg++ do to the membrane
“activation:?
Makes it both ligand and voltage gated channel.
AMPA receptor allows passage of?
Na+ influx
What activates AMPA receptors?
What modulates (inhibits) it?
EAAs
Benzos –> lower sodium entry.
Kainate receptors permit passage of what?
Na+ mostly, but also some Ca++
Which receptors are non-AMDA-receptors?
AMPA
Kainate
What is the characteristic of a non-NDMA EPSP? Why?
Typical EPSP with short onset or duration. It does not have anything blocking it, so Na+ enters easily and produces a normal EPSP.
What is the characteristic of an NDMA EPSP? Why?
Long latent period with long duration. It is normally blocked by Mg++, so the non-NDMA pathwya must occur first to increase IC Na+ and push the Mg++ off and allow Ca++ passage.
Where are non-NDMA receptors?
Primary sensory neurons
UPNs
What are NDMA receptors “critical” in?
Memory formation
Synaptic plasticity
3 groups of metabotropic receptors and their types:
Group 1 - Gq
Group 2/3 - Gi
What do the presynaptic and postsynaptic receptors effect in the EAA system?
Presynaptic - control NT release.
Postsynaptic - learning, memory, motor systems.
How is EAA broken down?
Presynaptic terminal releases it and glial cells reuptake and process to glutamine (like GAT1) and release it.
How is NO produced?
Ca++ released by NMDA receptors and act on calcineurin and activates NOS to make NO and citrulline from arginine..
What are the neural functions of NO?
Further increase NT release (diffuse back to presynaptic terminal).
Memory and CV/respiratory control in brainstem.
What immune cells produce NO?
Mo because it is toxic to invaders.
Problems w/ NO?
Unstable (half-life of 5 s)
Increase free radicals.
Toxic to neurons.
How is the membrane depolarized in a stroke?
What happens to EAA?
- Immediate loss of blood flow.
- Within minutes, oxygen drops to 0 near mitochondria –> ATP production stops.
- Na/K stops working.
- Depolarization of neurons.
- Continuous APs (for awhile).
- EAA released into cleft, but can’t be taken up into the postsynaptic cell because its uptake requires ATP. It accumulates.
How does Ca++ increase in the postsynaptic cell during an ischemic event?
Non-NMDA is activated, further depolarizes cell, and forces Mg++ out of Ca++ channel of the NMDA. This leads to increased Ca++.
Consequence of high IC Ca++ (4)
Increase in PLA
Activates mu-calpain
Activates calcineurin
Activates apoptotic pathway
What happens with an increase in PLA? (5)
Releases arachidonic acid and leads to damage of membrane.
Arachidonic acid leads to further Ca++ release.
ER stops making proteins.
eIF2a-kinase activation.
Mitochondrial dysfunction.
What happens with an increase in mu-calpain?
Proteolysis of structural proteins, enzymes, etc.
Leads to metabolic and structural problems in neurons.
How does Ca++ cause apoptosis?
It activates release of caspase 9, which activates caspase 9, which is the pro-apoptotic protein.
Why is reperfusion bad when there is excitotoxicity? (2)
- Mitochondria have no ATP, so they can’t use oxygen.
They oxygen builds up and becomes free radicals. - Allows for phosphorylation of eIFa2 which further activates the pro-apoptotic pathway and decreases protein synthesis.
