Causes of Excitotoxicity
- Increased/prolonged action potential firing (e.g. in status epilepticus)
- A malfunction in Calcium entry into the presynaptic cell (Voltage-gated calcium channels)
- Excess glutamate release (altered response to calcium/ altered vesicle-membrane action)
- Increased affinity for glutamate at binding site
- Increased receptor density
- Deficient cation selectivity
- Under certain conditions, AMPARs (normally only sodium permeable) become calcium permeable to calcium. This mainly happens when there is a change in the structure(/presence) of the GluR2 subunit
Stroke is becoming increasingly more common.
During ischaemia, the loss of ATP production causes non-functioning of glutamate re-uptake and a build up of extracellular glutamate. If ATP levels deplete too much, tranporter proteins may even act in reverse to pump more glutamate out of the cell. This causes high levels of NMDAR activation, which has been shown to be of benefit in ischaemic tissue (preventing axonal damage) in the short term. However, in the longer term, activation of NMDAR’s can cause neuronal death.