Glutamatergic Transmission

Question 1

What is glutamate?

Answer 1

A primary excitatory neurotransmitter.

Question 2

What is an NMDA receptor?

Answer 2

Ionotropic glutamate receptor.

Plays critical role in synaptic plasticity + learning and memory.

Question 3

What are 2 drugs that block NMDA receptors? And what can we call them?

Answer 3

KET and PCP

They are NMDA receptor antagonists.

Question 4

How many synapses in the brain are glutamate synapses?

Answer 4

Up to 70% of all synapses in the CNS

Question 5

What do NMDA receptor antagonists induce?

Answer 5

psychotic symptoms such as the positive, negative and cognitive symptoms seen in schiz:-
- Hallucinations
- Thought disorder
- flattened emotions
- cognitive impairments/attention/memory
- Electrophysiological abnormalities observed in patients with schiz.

Question 6

What does Dysbindin do?

Answer 6

• A susceptibility gene for schiz
• Regulates vGluT ( vesicular glutamate transporter) , crucial for glutamate neurotransmission
• proper storage and release of glutamate to synapse

Question 7

What does DISC-1 and Neuregulin do?

Answer 7

• Genes involved in NMDA receptor trafficking to post-synaptic membrane
• essential for proper synaptic function.
• DISC-1 also affects transport of synaptic vesicles in presynaptic glutamate terminals -> crucial for neurotransmitter release

Question 8

What does DAOA do?

Answer 8

• Enzyme that degrades D-Serine, which is a co-agonist required for NMDA function.
• Reduced levels of D-Serine could impair NMDA receptor function + contribute to symptoms.

Question 9

What does NMDA R require?

Answer 9

2 co-agonists; Glutamate + glycine ( or D-serine), to open the channel.

(and allow influx of calcium ions in)

Question 10

Issue with direct stimulation of NMDA R?

Answer 10

Can lead to excessive activation + excitotoxicity -> damaging neurones and cell death.

Question 11

Why is indirect stimulation better and how?

Answer 11

By stimulating the glycine modulation site, more precise regulation of NMDA R activation.

Question 12

Role of Glycine modulatory sites

Answer 12

• Located on seperate domain of the receptor
• Enhance binding of glycine to co-agonist site
• Increased sensitivity to levels of glycine allows for more controlled activation in responses to glutamate release.