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BMSC - Neuroanatomy > Excitotoxicity > Flashcards

Excitotoxicity Flashcards

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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
What are the clinical implications of domoic acid poisoning?
Short term memory loss Brain damage Death
26
Where does neural necrosis occur with ASP?
Hippocampus | Amygdala
27
At which sites does domoic acid act as an agonist?
AMPARs | KARs
28
What does domoic acid induced activation of AMPA/KARs lead to?
Increased intracellular Ca2+ and therefore glutamate release
29
Kainate is more potent than domoic acid at KARs. | true/false
False | DA is 20x more potent that kainate
30
Domoic acid is readily removed by glutamate transporters | True/false
False | Not readily removed and is therefore toxic
31
Which amino acid does cyanobacteria produce?
Beta-methylamino-alanine (BMAA)
32
BMAA is the cause of which clinical condition?
ALS
33
How does BMAA kill motor neurons?
Activates AMPA-KARs | Boosts ROS production
34
NMDAR antagonists increase ischaemic damage in vivo | True/false
False | They reduce it
35
Glutamate toxicity is predominantly mediated through.....
NMDARs
36
Which is the most sensitive to glutamate: AMPAR, KAR, NMDAR
NMDAR
37
What is the EC50?
Concentration that elicits 50% response
38
Which pre-synaptic abnormalities may lead to excessive excitation?
Increased firing of APs Mutation of VGCC Altered req for Ca2+ influx
39
Which post-synaptic abnormalities lead to excessive excitation?
Increased affinity of glutamate binding site Increased density of glutamate receptors Deficient cation selectivity
40
Which subunits to AMPARs normally contain?
GluA2 subunits(R)
41
GluA2 (R) subunits are impermeable to calcium true/false
True
42
Which AMPAR subunits would be permeable to calcium?
GluA2(Q)
43
Compare apoptosis and necrosis
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
Which mediators does the mitochondria release which leads to apoptosis?
Cytochrome C Caspase 9 Aif (apoptosis inducing factor)
45
What do mitochondria buffer within cells?
Ca2+
46
What does activation of NOS by sever insult lead to?
Increased mitochondrial Ca2+, superoxide formation and peroxynitrite (ONOO-) formation
47
Cellular damage caused by ONOO- leads to....
Activation of poly-ADP-ribose polymerase (PARS)
48
What does mitochondrial Ca2+ accumulation then cause?
Activation and of permeability transition pore (PTP)
49
Why does PARS activation lead to mitochondrial dysfunction?
Depletes ATP and NAD which are required for normal functioning
50
What does elimination of NMDARs cause in vivo?
Widespread apoptosis in developing neurons
51
Which curve do NMDAR responses follow?
hermetic-dose-response
52
Which NMDARs are pro-survival: synaptic or extra-synaptic?
Synaptic
53
Why are extra-synaptic NMDARs linked to pro-death signalling?
They shut down CREB functioning and trigger mitochondrial depolarisation
54
How does NMDAR activity promote survival through Akt?
NMDAR enhances PI3K mediated conversion to PIP2 to PIP3 | PIP3 then activates Akt which reduces cell death and promotes growth
55
What are the main inhibitory targets for Akt?
GSK-3-beta BAD p53
56
Which CREB-target genes are implicated in NMDAR-dependent neuroprotection?
AID (Activity-dependent inhibitor of death) NFAT (nuclear factor of activated T cells)
57
Neurons with higher basal NMDAR can withstand more/less oxidative stress?
More
58
What effect does synaptic activity have on mitochondrial fission?
Enhances
59
What effect does synaptic activity have on mitochondrial mobility?
Reduction
60
Where does synaptic activity localise mitochondria to?
Dendritic spines
61
Does synaptic activity increase or decrease BDNF expression?
Increase (this is neuroprotective)
62
Ca2+ efflux from neurons occurs via....
PMCA and NCX | plasma membrane Ca2+ ATPase and Na+-Ca2+ exchangers
63
Are calpains activated or inhibited by excessive NMDAR Ca2+ influx?
Activated
64
Which isoform of NCX do calpains cleave?
NCX3 (impaired function)
65
How do calpains affect PMCA?
Inactivate
66
Where do PMCAs normally get energy from?
ATP hydrolysis
67
Give examples of stress-activated protein kinases (SAPKs)
P38 MAPK | JNK
68
Which compound is involved in NMDAR dependent P38 MAPK activation in cerebellar neurons?
nNOS (neuronal nitric oxide synthase)
69
Compare synaptic and extrasynaptic NMDARs
``` 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
Describe the composition of NMDARs
One NR1 subunits one or more NR2 subunits (NR2A/B/C/D) With/out NR3 subunit
71
Which NR subunit types predominate in the hippocampus?
A and B | synaptic, extraysnaptic
72
What is memantine?
NMDAR antagonist
73
In spinal motor atrophy mice, daily administration of NMDA caused....
Improvements in motor behaviour and lifespan | Reduced motor neuron death
74
Huntington's disease shows increased/decreased NMDAR?
Increased extrasynaptic

BMSC - Neuroanatomy (17 decks)

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