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BMSC - Neuroanatomy > Excitotoxicity > Flashcards

Excitotoxicity Flashcards

1
Q

What is the main excitatory neurotransmitter in the brain?

A

Glutamate

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2
Q

Define excitotoxicity

A

Cell death resulting from the toxic actions of excitatory amino acids

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3
Q

Give examples of amino acids which cause ecotoxicity

A 
Cysteine
Cysteine sulfonate 
Cysteic acid 
Homocysteine 
Glutamate
Aspartate
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4
Q

Where are neurotransmitters synthesised?

A

Presynaptic terminal

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5
Q

Which ion influxes in response to depolarisation?

A

Calcium

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6
Q

Outline synaptic transmission

A

NT synthesised and stored in presynaptic terminal.
AP depolarises the presynaptic terminal.
Ca2+ influx.
Release of NT via exocytosis and diffusion to postsynaptic membrane.
Interacts with postsynaptic receptors.
NT degradation and reuptake

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7
Q

How is excess glutamate removed from the synapse?

A

Reuptake by ATP dependent transporters

Uptake into glial cells

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8
Q

Which channels open in the axon to allowed Na+ influx?

A

Voltage gated Na channels

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9
Q

What causes repolarisation of the membrane in synaptic transmission?

A

Outflow of K+

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10
Q

Describe the extracellular glutamate level (under normal circumstance)

A

Low

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11
Q

How is cytosolic glutamate transported into vesicles?

A

Vesicular ATP-dependent glutamate transporters

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12
Q

What happens to glutamate uptake during ischaemia?

A

Stop or reversal

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13
Q

What are the three main types of glutamate receptor?

A

Kainate
AMPAR
NMDAR

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14
Q

What are NMDARs permeable to?

A

Ca2+

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15
Q

Which ions block NMDARs?

A

Mg2+

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16
Q

NMDARs do not contribute to basal transmission true/false

A

True (as Mg2+ present to block receptors)

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17
Q

How are NMDARs activated?

A

Intense synaptic activity activates AMPARs to cause depolarisation and alleviation of Mg2+

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18
Q

How do NMDARs mediate excitotoxicity?

A

Due to high Ca2+ permeability

Incomplete desensitisation

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19
Q

What clinical scenarios are associated with excessive NMDAR activation?

A

Ischaemia

Chronic neurodegeneration

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20
Q

Which receptors are responsible for fast excitation?

A

AMPAR

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21
Q

Which receptors are responsible for slow excitation?

A

NMDAR

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22
Q

What is meant by a “dual component EPSC”?

A

Has both slow NMDAR and fast AMPAR mediated components

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23
Q

In which foods does domoic acid accumulate?

A

Shellfish

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24
Q

Which compound is associated with amnesic shellfish poisoning (ASP) ?

A

Domoic acid

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25
Q

What are the clinical implications of domoic acid poisoning?

A

Short term memory loss
Brain damage
Death

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26
Q

Where does neural necrosis occur with ASP?

A

Hippocampus

Amygdala

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27
Q

At which sites does domoic acid act as an agonist?

A

AMPARs

KARs

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28
Q

What does domoic acid induced activation of AMPA/KARs lead to?

A

Increased intracellular Ca2+ and therefore glutamate release

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29
Q

Kainate is more potent than domoic acid at KARs.

true/false

A

False

DA is 20x more potent that kainate

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30
Q

Domoic acid is readily removed by glutamate transporters

True/false

A

False

Not readily removed and is therefore toxic

31
Q

Which amino acid does cyanobacteria produce?

A

Beta-methylamino-alanine (BMAA)

32
Q

BMAA is the cause of which clinical condition?

A

ALS

33
Q

How does BMAA kill motor neurons?

A

Activates AMPA-KARs

Boosts ROS production

34
Q

NMDAR antagonists increase ischaemic damage in vivo

True/false

A

False

They reduce it

35
Q

Glutamate toxicity is predominantly mediated through…..

A

NMDARs

36
Q

Which is the most sensitive to glutamate: AMPAR, KAR, NMDAR

A

NMDAR

37
Q

What is the EC50?

A

Concentration that elicits 50% response

38
Q

Which pre-synaptic abnormalities may lead to excessive excitation?

A

Increased firing of APs
Mutation of VGCC
Altered req for Ca2+ influx

39
Q

Which post-synaptic abnormalities lead to excessive excitation?

A

Increased affinity of glutamate binding site
Increased density of glutamate receptors
Deficient cation selectivity

40
Q

Which subunits to AMPARs normally contain?

A

GluA2 subunits(R)

41
Q

GluA2 (R) subunits are impermeable to calcium true/false

A

True

42
Q

Which AMPAR subunits would be permeable to calcium?

A

GluA2(Q)

43
Q

Compare apoptosis and necrosis

A

Apoptosis vs Necrosis
Indiv cells /// groups of cells
Physiological stimuli /// non-physiological stimuli
No inflammation /// inflammation
Shrinkage of cytoplasm and condensed nuclei /// swelling of both
Blebbing /// loss of membrane
Active /// passive

44
Q

Which mediators does the mitochondria release which leads to apoptosis?

A

Cytochrome C
Caspase 9
Aif (apoptosis inducing factor)

45
Q

What do mitochondria buffer within cells?

A

Ca2+

46
Q

What does activation of NOS by sever insult lead to?

A

Increased mitochondrial Ca2+, superoxide formation and peroxynitrite (ONOO-) formation

47
Q

Cellular damage caused by ONOO- leads to….

A

Activation of poly-ADP-ribose polymerase (PARS)

48
Q

What does mitochondrial Ca2+ accumulation then cause?

A

Activation and of permeability transition pore (PTP)

49
Q

Why does PARS activation lead to mitochondrial dysfunction?

A

Depletes ATP and NAD which are required for normal functioning

50
Q

What does elimination of NMDARs cause in vivo?

A

Widespread apoptosis in developing neurons

51
Q

Which curve do NMDAR responses follow?

A

hermetic-dose-response

52
Q

Which NMDARs are pro-survival: synaptic or extra-synaptic?

A

Synaptic

53
Q

Why are extra-synaptic NMDARs linked to pro-death signalling?

A

They shut down CREB functioning and trigger mitochondrial depolarisation

54
Q

How does NMDAR activity promote survival through Akt?

A

NMDAR enhances PI3K mediated conversion to PIP2 to PIP3

PIP3 then activates Akt which reduces cell death and promotes growth

55
Q

What are the main inhibitory targets for Akt?

A

GSK-3-beta
BAD
p53

56
Q

Which CREB-target genes are implicated in NMDAR-dependent neuroprotection?

A

AID (Activity-dependent inhibitor of death)

NFAT (nuclear factor of activated T cells)

57
Q

Neurons with higher basal NMDAR can withstand more/less oxidative stress?

A

More

58
Q

What effect does synaptic activity have on mitochondrial fission?

A

Enhances

59
Q

What effect does synaptic activity have on mitochondrial mobility?

A

Reduction

60
Q

Where does synaptic activity localise mitochondria to?

A

Dendritic spines

61
Q

Does synaptic activity increase or decrease BDNF expression?

A

Increase (this is neuroprotective)

62
Q

Ca2+ efflux from neurons occurs via….

A

PMCA and NCX

plasma membrane Ca2+ ATPase and Na+-Ca2+ exchangers

63
Q

Are calpains activated or inhibited by excessive NMDAR Ca2+ influx?

A

Activated

64
Q

Which isoform of NCX do calpains cleave?

A

NCX3 (impaired function)

65
Q

How do calpains affect PMCA?

A

Inactivate

66
Q

Where do PMCAs normally get energy from?

A

ATP hydrolysis

67
Q

Give examples of stress-activated protein kinases (SAPKs)

A

P38 MAPK

JNK

68
Q

Which compound is involved in NMDAR dependent P38 MAPK activation in cerebellar neurons?

A

nNOS (neuronal nitric oxide synthase)

69
Q

Compare synaptic and extrasynaptic NMDARs

A 
Synaptic vs Extrasynaptic 
Ca2+ tolerated /// triggers cell death 
Activates ERK /// inactivates ERK 
Activates CREB dependent gene expression /// cause CREB dephosphorylation 
Activates PI3K/Akt /// doesn't
70
Q

Describe the composition of NMDARs

A

One NR1 subunits
one or more NR2 subunits (NR2A/B/C/D)
With/out NR3 subunit

71
Q

Which NR subunit types predominate in the hippocampus?

A

A and B

synaptic, extraysnaptic

72
Q

What is memantine?

A

NMDAR antagonist

73
Q

In spinal motor atrophy mice, daily administration of NMDA caused….

A

Improvements in motor behaviour and lifespan

Reduced motor neuron death

74
Q

Huntington’s disease shows increased/decreased NMDAR?

A

Increased extrasynaptic

BMSC - Neuroanatomy (17 decks)

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