Lecture 10 Flashcards
What are the types of glutamate ligand-gated ion channels?
- NMDA, AMPA, kainate
What type of transmission are the glutamate ligand-gated ion channels responsible for?
Fast, excitatory transmission
How is glutamate synthesised?
1) uptake of glutamate into glial cells 2) conversion of glutamate to glutamine via glutamine synthetase 3) neuron takes up glutamine 4) glutamate production - glutamine to glutamate via glutaminase - glutamate from tricarboxylic acid cycle
How is glutamate activity terminated?
Via EAAT (excitatory amino acid transporter) - 1-2 (postsynaptic neuron)- 3-4 (glial cell)
What is the structure of the glutamate receptors?
Tetrameric
Why is the NMDA receptor unusual?
Requires two agonists in order for it to be activated
What are the co-agonists of the NMDA receptor?
- glycine, D-serine
What is the role of the Mg2+ ion in the NMDA receptor?
drawn to neuronal intracellular environment, block NMDA receptor activation under regular circumstances
What do we known from NMDA receptor subunit diversity?
Determines the properties and function of the NMDA receptor e.g. ion conductance/sensitivity, agonist potency, deactivation rate
How does AMPA receptor subunit diversity affect function?
Affects the current/voltage relationship through the receptor - rectifiers= flow of ions is favoured in one direction - linear= similar current produced at different voltages
How does the AMPA receptor index change with age?
The permeability to ions e.g. Ca2+ decreases but the flow of other ions e.g. Na+= increased transmission
What are the roles of glutamate?
- mediates majority of fast excitatory synaptic transmission in CNS - cognition, movement, central cardiovascular, thermoregulatory and respiratory control - learning and memory - neurodevelopmental, neurological and neurodegenerative conditions - target of drugs of abuse e.g. ketamine
What is the electrophysiological evidence for silent synapses?
Lack of a response to glutamate up until a positive charge has been reached
What are silent synapses?
- lack AMPA receptors on the post-synaptic membrane - does not transmit info at hyperpolarised membrane potential due to Mg2+ block - AMPA receptors may be stored in vesicles or at extrasynaptic sites
How do silent synapses become unsilent?
- membrane depolarisation triggers NMDA activation - NMDA activation= Ca2+ influx - Ca2+ influx results in the movement of AMPA receptors which become inserted into the membrane
How do we determine that the initial activation of silent synapses is due to NMDA and not AMPA activation?
Use of an NMDA antagonist e.g. D-APV inhibits activity
What is the pairing procedure?
Induces long-term potentiation by simultaneously stimulating glutamate fibres and activating the NMDA receptor
What is the antibody evidence of native AMPA receptors?
- green antibodies reveal AMPA receptors present before depolarisation - after depolarisation, new AMPA receptors are stained red - use of an NMDA antagonist reveals fewer new AMPA receptors
What is long-term potentiation?
A persistent increase in synaptic strength following high-frequency stimulation of a synapse.
What is long-term depression?
A stable and enduring decrease in the effectiveness of synapses
Where does long-term potentiation and depression occur?
Hippocampus
What happens to LTP when an NMDA antagonist e.g. AP5 is used?
Inhibited
How does an NMDA antagonist affect the Morris Water Maze test?
- D, L-AP5= inhibits spatial learning so animal swims around aimlessly - L-AP5 (inactive isomer)= no effect on spatial learning
How does trafficking of AMPA receptors regulate synaptic strength?
Exocytosis/endocytosis of AMPA receptor subunits to the postsynaptic membrane
What are the implications of AMPA trafficking at synapses?
- brain development - learning and memory - pain - cerebral ischemia (stroke) - Alzheimer’s disease (LTD may lead to synapse loss)
Why would an NMDA antagonist be used to treat Alzheimer’s?
- overexcited receptors= excess Ca2+ - excessive Ca2+ influx can damage neurones- inhibits NMDA receptors only when they are excessively active - regular functioning is preserved
