Excitotoxicity Flashcards
What is the main excitatory nT in the brain?
Glutamate
What is glutamate key for?
Many physiological processes e.g. LTP and neurodevelopment
What is excitotoxicity?
Cell death resulting from the toxic actions of excitatory amino acids
What amino acids have been linked to excitatory toxic damage?
Cysteine Cysteine sulfonate Cysteic acid Homocysteine Glutamate Aspartate
Can oral glutamate be damaging?
Yes; can produce neurodegeneration in vivo
What diseases have been linked to excitotoxic damage?
Brain trauma Heavy metal toxicity Brain tumours Neurodegenerative disease CNS infections Autoimmune Stroke
What channel does an action potential at a synapse initially open?
Sodium channel - depolarization
Then K+ opens to result in repolarization
How is excess synaptic glutamate removed to avoid toxicity?
Reuptake into the presynaptic terminal
Uptake into glial cells (main route) - located close to excitatory synapse
Describe the presynaptic terminal action potential
Action potential fires in axon
Voltage gated Na+ open and Na+ floods in
DEPOLARIZATION
Delayed opening of K+ channels, K+ floods out
REPOLARIATION
Voltage dependent Ca2+ channels open, calcium influx
nT RELEASE
Describe the respective neuronal levels of glutamate
Vesicles; 100mM
Cytosol; 10mM
Extracellular 1 micromole
Synaptic space; 2mM
Are extracellular glutamate levels kept high or low?
Low; prevent endogenous toxicity
How is glutamate removed from the extracellular space to keep levels low?
ATP-dependent glutamate transporters (on plasma membrane)
THEREFORE; effective levels of ATP are required for glutamate transport and prevention of excitotoxicity
In what situations is glutamate uptake stopped or reversed?
Metabolic compromise; no ATP production
Mitochondria failure
E.g. ischaemic damage such as a stroke
What are the different types of glutamate receptors present on the postsynaptic neuron?
Metabotropic receptors (mGluR) - modulates intracellualr signal transduction Ionotropic receptors (GluR) - AMPA, kainate and NMDA Open cation channels
What cation channels do AMPA and NMDA open respectively?
AMPA = Na+ NMDA = Ca2+ and Na+ as well as K+ efflux
Which glutamate receptor plays a key role in excitoxicity?
NMDA
Describe the opening of NMDA receptors
NMDARs are highly permeable to Ca2+, therefore NMDAr activation allows Ca2+ entry
NMDARs are blocked by Mg2+ ions in a voltage dependent manner
NMDAr channel opening requires sufficient depolarization
Do NMDARs contribute to basal synaptic transmission?
No, Mg2+ block it
When will NMDARs contribute to synaptic transmission?
During intense synaptic activity, AMPARs are activated and if there is sufficient depolarization, then the Mg2+ is displaced and the NMDA opens
How do NMDARs mediate excitotoxicity?
High Ca2+ permeability and incomplete desensitisation
What does pathological activation of NMDARs contribute to?
Neuronal death after acute excitotoxic trauma
Chronic neurodegenerative disease
What is the dual component of a a glutamate mediated EPSC?
Fast AMPAR mediated
Slow NMDAR mediated
What are the 4 main types of glial cells in the CNS?
Astrocytes
Oligodendrocytes
Ependymal cells
Microglia
What are possible malfunctions are the glutamatergic synapse?
Excessive excitation; excitotoxicity
Deficient excitation