OCB03-2008 GLUTAMATE

Question 1

Why is a neuronal output described as an “integrated response”?

Answer 1

Determined by the NUMBER of excitatory and inhibitory synaptic inputs and the STRENGTH of each individual input

Question 2

How can the timing of neuronal inputs affect the post-synaptic output?

Answer 2

Excitatory inputs close together = summation

Inhibitory inputs can dampen down the excitatory input/depolarisation if they occur simultaneously

Question 3

What is glutamate and its importance in the nervous system?

Answer 3

Amino acid

Major excitatory neurotransmitter in the CNS

Question 4

Describe some prominent glutamatergic pathways in the brain.

Answer 4

Cortico-cortical pathways - inflammation processing centres and modulation of neuronal activity

Between thalamus and cortex

Extrapyramidal pathway (cortex and striatum) - regulates involuntary movement

Question 5

What psychiatric conditions are glutamatergic pathways implicated in? (4)

Answer 5

Depression

Anxiety

Schizophrenia

Drug addiction

Question 6

What main functions is glutamate involved in? (3)

Answer 6

Memory

Emotion

Cognition

Question 7

Can glutamate cross the blood-brain barrier?

Answer 7

No

Question 8

How can glutamate synthesised in the CNS?

Answer 8

Metabolism of glucose (TCA cycle)

From glutamine in astrocytes

Question 9

What is the concentration of glutamate in neuron cytoplasm?

Answer 9

1mM

Question 10

What is the concentration of glutamate in presynaptic vesicles?

Answer 10

20-100mM

Question 11

Describe the process of synaptic transmission in glutamatergic neurons.

Answer 11

AP depolarises neuron causing voltage-gated Ca channels to open = Ca++ influx

Exocytosis of presynaptic glutamate and diffusion across synapse to interact with postsynaptic receptors

Glutamate diffuses out of synaptic cleft and taken up by glutamate transporters on astrocytes

Question 12

Describe the process of the recycling of glutamate after transmission.

Answer 12

Glutamate taken up into astrocytes by glutamate transporters

Glu –> Gln by glutamine synthase

Gln extruded by glutamine transporters into extracellular space

Gln taken up into neurons by glutamine transporters

Gln –> Glu by glutaminase

Question 13

What is essential to terminate synaptic transmission via glutamate?

Answer 13

Uptake of Glu by astrocytes via glutamate transporters

Question 14

What are the two main types of glutamate receptor?

Answer 14

Ionotropic

Metabotropic/7TMGPCR

Question 15

Describe glutamate ionotropic receptors.

Answer 15

Fast transmission

Na+, K+, Ca+ allowed through (depolarise membrane)

4 sub-units

Post-synaptic

Question 16

What are the three classes of ionotropic glutamate receptor?

Answer 16

NMDA (N-methyl-D-aspartate) receptors

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors

Kainate receptors

Question 17

Where is kainate commonly found in nature?

Answer 17

Seaweed

Question 18

Which ionotropic glutamate receptors are often co-localised together at synapses?

Answer 18

NMDA and AMPA

Question 19

What is the main function of metabotropic glutamate receptors?

Answer 19

Modulate excitation and synaptic transmission

Question 20

Describe the activation of AMPA receptors.

Answer 20

Rapid activation and rapid decay ~1-2ms

Usually Na+ depolarisation

Question 21

Describe the activation of kainate receptors.

Answer 21

Rapid activation and rapid decay ~1-2ms

Usually Na+ depolarisation

Question 22

Describe the activation of NMDA receptors.

Answer 22

Slower onset and slower decay of several hundred ms

High affinity Glu binding

Na+ and Ca++ influx

Question 23

What is the Kd of NMDA receptors for glutamate?

Answer 23

5nM

Question 24

What is the importance of Ca++ influx in NMDA receptor activation?

Answer 24

Modulates activity of Ca-dependent kinases and phosphatases involved in longer term changes in neuronal behaviours

Eg gene expression, learning and memory

Question 25

What would a block in AMPA or kainate receptors likely cause?

Answer 25

Major inhibitory effects on CNS

Question 26

What would a block in NMDA receptors likely cause?

Answer 26

Effects on behaviour and memory

Question 27

Describe the full EPSP in excitatory glutamatergic transmission.

Answer 27

Fast onset due to AMPA or kainate receptors Long duration due to NMDA receptors

Question 28

Why do NMDA receptors have a slow onset and slow decay?

Answer 28

Blocked by extracellular Mg++ ions at normal/low membrane potentials

Question 29

The activity of which glutamate receptors are likely to represent the glutamate concentration in the synapse and why?

Answer 29

AMPA (and kainate) receptors Low glutamate affinity so bind only in high concentrations and dissociate rapidly

Question 30

What is the Kd of AMPA receptors for glutamate?

Answer 30

200nM

Question 31

How many metabotropic glutamate receptors are there?

Answer 31

8

Question 32

What is the function of presynaptic mGluR?

Answer 32

Inhibit voltage-gated Ca channels = decreased Ca++ influx Less neurotransmitter release of other neurons or itself

Question 33

What G protein are mGluRs coupled to?

Answer 33

Gi (inhibitory)

Question 34

What are the functions of the G protein coupled to mGluRs?

Answer 34

α-GTP = inhibit adenylyl cyclase βγ: Reduce activity of voltage-gated Ca channels Reduce exocytosis presynaptically Slow hyperpolarisation postsynaptically via K channels

Question 35

Describe how glutamate excitotoxicity/ischaemic cell death occurs.

Answer 35

Ischaemia = dramatic decrease in ATP production ATPase pumps stop working = membrane potential depolarises so glutamate transporters stop working Increased extracellular glutamate NMDA receptors activated resulting in massive Ca++ influx Neuronal Ca++ buffering/extrusion capacity overcome Activation of degradative biochemical processes (eg Calpain) Cell death in mins