OCB03-2008 GLUTAMATE Flashcards

1
Q

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

A

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

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2
Q

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

A

Excitatory inputs close together = summation

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

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3
Q

What is glutamate and its importance in the nervous system?

A

Amino acid

Major excitatory neurotransmitter in the CNS

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4
Q

Describe some prominent glutamatergic pathways in the brain.

A

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

Between thalamus and cortex

Extrapyramidal pathway (cortex and striatum) - regulates involuntary movement

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5
Q

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

A

Depression

Anxiety

Schizophrenia

Drug addiction

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6
Q

What main functions is glutamate involved in? (3)

A

Memory

Emotion

Cognition

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7
Q

Can glutamate cross the blood-brain barrier?

A

No

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8
Q

How can glutamate synthesised in the CNS?

A

Metabolism of glucose (TCA cycle)

From glutamine in astrocytes

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9
Q

What is the concentration of glutamate in neuron cytoplasm?

A

1mM

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10
Q

What is the concentration of glutamate in presynaptic vesicles?

A

20-100mM

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11
Q

Describe the process of synaptic transmission in glutamatergic neurons.

A

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

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12
Q

Describe the process of the recycling of glutamate after transmission.

A

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

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13
Q

What is essential to terminate synaptic transmission via glutamate?

A

Uptake of Glu by astrocytes via glutamate transporters

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14
Q

What are the two main types of glutamate receptor?

A

Ionotropic

Metabotropic/7TMGPCR

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15
Q

Describe glutamate ionotropic receptors.

A

Fast transmission

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

4 sub-units

Post-synaptic

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16
Q

What are the three classes of ionotropic glutamate receptor?

A

NMDA (N-methyl-D-aspartate) receptors

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

Kainate receptors

17
Q

Where is kainate commonly found in nature?

A

Seaweed

18
Q

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

A

NMDA and AMPA

19
Q

What is the main function of metabotropic glutamate receptors?

A

Modulate excitation and synaptic transmission

20
Q

Describe the activation of AMPA receptors.

A

Rapid activation and rapid decay ~1-2ms

Usually Na+ depolarisation

21
Q

Describe the activation of kainate receptors.

A

Rapid activation and rapid decay ~1-2ms

Usually Na+ depolarisation

22
Q

Describe the activation of NMDA receptors.

A

Slower onset and slower decay of several hundred ms

High affinity Glu binding

Na+ and Ca++ influx

23
Q

What is the Kd of NMDA receptors for glutamate?

A

5nM

24
Q

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

A

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

Eg gene expression, learning and memory

25
Q

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

A

Major inhibitory effects on CNS

26
Q

What would a block in NMDA receptors likely cause?

A

Effects on behaviour and memory

27
Q

Describe the full EPSP in excitatory glutamatergic transmission.

A

Fast onset due to AMPA or kainate receptors

Long duration due to NMDA receptors

28
Q

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

A

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

29
Q

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

A

AMPA (and kainate) receptors

Low glutamate affinity so bind only in high concentrations and dissociate rapidly

30
Q

What is the Kd of AMPA receptors for glutamate?

A

200nM

31
Q

How many metabotropic glutamate receptors are there?

A

8

32
Q

What is the function of presynaptic mGluR?

A

Inhibit voltage-gated Ca channels = decreased Ca++ influx

Less neurotransmitter release of other neurons or itself

33
Q

What G protein are mGluRs coupled to?

A

Gi (inhibitory)

34
Q

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

A

α-GTP = inhibit adenylyl cyclase

βγ:
Reduce activity of voltage-gated Ca channels
Reduce exocytosis presynaptically
Slow hyperpolarisation postsynaptically via K channels

35
Q

Describe how glutamate excitotoxicity/ischaemic cell death occurs.

A

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