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BMSc - Neuropharmacology and Behaviour > Excitotoxicity > Flashcards

Excitotoxicity Flashcards

1
Q

What is the main excitatory nT in the brain?

A

Glutamate

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2
Q

What is glutamate key for?

A

Many physiological processes e.g. LTP and neurodevelopment

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3
Q

What is excitotoxicity?

A

Cell death resulting from the toxic actions of excitatory amino acids

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4
Q

What amino acids have been linked to excitatory toxic damage?

A 
Cysteine 
Cysteine sulfonate
Cysteic acid
Homocysteine 
Glutamate 
Aspartate
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5
Q

Can oral glutamate be damaging?

A

Yes; can produce neurodegeneration in vivo

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6
Q

What diseases have been linked to excitotoxic damage?

A 
Brain trauma
Heavy metal toxicity
Brain tumours
Neurodegenerative disease
CNS infections
Autoimmune
Stroke
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7
Q

What channel does an action potential at a synapse initially open?

A

Sodium channel - depolarization

Then K+ opens to result in repolarization

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8
Q

How is excess synaptic glutamate removed to avoid toxicity?

A

Reuptake into the presynaptic terminal

Uptake into glial cells (main route) - located close to excitatory synapse

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9
Q

Describe the presynaptic terminal action potential

A

Action potential fires in axon
Voltage gated Na+ open and Na+ floods in
DEPOLARIZATION
Delayed opening of K+ channels, K+ floods out
REPOLARIATION
Voltage dependent Ca2+ channels open, calcium influx
nT RELEASE

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10
Q

Describe the respective neuronal levels of glutamate

A

Vesicles; 100mM
Cytosol; 10mM
Extracellular 1 micromole
Synaptic space; 2mM

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11
Q

Are extracellular glutamate levels kept high or low?

A

Low; prevent endogenous toxicity

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12
Q

How is glutamate removed from the extracellular space to keep levels low?

A

ATP-dependent glutamate transporters (on plasma membrane)

THEREFORE; effective levels of ATP are required for glutamate transport and prevention of excitotoxicity

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13
Q

In what situations is glutamate uptake stopped or reversed?

A

Metabolic compromise; no ATP production
Mitochondria failure
E.g. ischaemic damage such as a stroke

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14
Q

What are the different types of glutamate receptors present on the postsynaptic neuron?

A 
Metabotropic receptors (mGluR) - modulates intracellualr signal transduction 
Ionotropic receptors (GluR) - AMPA, kainate and NMDA
Open cation channels
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15
Q

What cation channels do AMPA and NMDA open respectively?

A 
AMPA = Na+ 
NMDA = Ca2+ and Na+ as well as K+ efflux
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16
Q

Which glutamate receptor plays a key role in excitoxicity?

A

NMDA

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17
Q

Describe the opening of NMDA receptors

A

NMDARs are highly permeable to Ca2+, therefore NMDAr activation allows Ca2+ entry
NMDARs are blocked by Mg2+ ions in a voltage dependent manner
NMDAr channel opening requires sufficient depolarization

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18
Q

Do NMDARs contribute to basal synaptic transmission?

A

No, Mg2+ block it

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19
Q

When will NMDARs contribute to synaptic transmission?

A

During intense synaptic activity, AMPARs are activated and if there is sufficient depolarization, then the Mg2+ is displaced and the NMDA opens

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20
Q

How do NMDARs mediate excitotoxicity?

A

High Ca2+ permeability and incomplete desensitisation

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21
Q

What does pathological activation of NMDARs contribute to?

A

Neuronal death after acute excitotoxic trauma

Chronic neurodegenerative disease

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22
Q

What is the dual component of a a glutamate mediated EPSC?

A

Fast AMPAR mediated

Slow NMDAR mediated

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23
Q

What are the 4 main types of glial cells in the CNS?

A

Astrocytes
Oligodendrocytes
Ependymal cells
Microglia

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24
Q

What are possible malfunctions are the glutamatergic synapse?

A

Excessive excitation; excitotoxicity

Deficient excitation

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25
Q

What is domoic acid?

A

Glutamate analog associated with certain harmful algal blooms

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26
Q

Are there any examples of human cases of excitotoxic damage due to oral ingestion?

A

Yes; domoic acid (glutamate analog) is assoc with harmful algal blooms and therefore can accumulate in high concentrations in tissues of plankton feeders (Shellfish)
DA is assoc with the phenomenon of amnesic shellfish poisoning (ASP)

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27
Q

In mammals, what is the action of DA?

A

Acts as a neurotoxin, causing a short-term memory loss, brain damage and in severe cases death

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28
Q

What do postmortem studies of people show of those who have been affected by DA?

A

Neuronal necrosis in hippocampus and amygdala

Survivors have irreversible loss of short term memory

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29
Q

What is the mechanism of action of domoic acid?

A

An agonist at non-NMDA receptors (AMPA/Kainate)

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30
Q

What action does DA have on AMPA/ Kainate receptors?

A

Increases intracellular Ca2+ promoting release of glutamate

This released glutamate activates NMDARs

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31
Q

What is the potency of DA at a neuronal level?

A

DA is up to 20 fold more potent than kainate at KARs

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32
Q

Is DA readily removed from the synapse?

A

No; not readily removed by glutamate transporters and is therefore very toxic

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33
Q

What is BMAA?

A

A neurotoxin that is very similar to the amino alanina

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34
Q

What produces BMAA?

A

Cyanobacteria

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35
Q

What are the sequelae of BMAA ingestion?

A

ALS/ PD-LB dementia complex

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36
Q

Where can BMAA be found?

A

Cyad seeds and fruit bats

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37
Q

How does BMA cause ALS like symptoms?

A

Kills motor neurones by activated AMPA and kainate glutamate receptors and by the formation of oxygen free radicals

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38
Q

What is the evidence that excitotoxicity is implicated in ischaemic brain damage?

A

After a stroke, extracellular levels of glutamate increase by up to 100 micromoles
In stroke models, NMDAR antagonists can reduce ischaemic neuronal damage in vivo

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39
Q

Which glutamate receptors are most sensitive to glutamate?

A

NMDARs; EC50 around 2micromoles
AMPA/KAR EC50 around 300 micromoles
NMDARs are the most sensitive to glutamate, and this is why they are most implicated in excitotoxic damage

40
Q

What changes occur at the presynaptic membrane that are linked to excitotoxic damage?

A

Increased firing rate of action potential; enhanced nT release
Change in calcium influx mediated by voltage dependent calcium channels (threshold lowered)
Altered glutamate release; altered requirement for calcium influx, altered vesicle loading

41
Q

Is there anything that can enhance glutamate toxicity?

A

Reverse uptake; outpouring of glutamate

Depletion of cytosolic ATP

42
Q

What changes can occur at the postsynaptic membrane that can lead to excitotoxic damage?

A

Increased affinity of glutamate binding site
Increased density of glutamate receptors
Deficient cation selectivity of the ionophore (R/Q editing) - particularly AMPA receptors

43
Q

How can the ion selectivity at glutamate (AMPA) gated channels change?

A

Under certain conditions, AMPARs can become permeable to Ca2+
If the RNA editing fails, the GluA2 subunit changes from an R to a Q
The Q form of GluA2 is calcium permeable

44
Q

Why are most AMPA receptors impermeable to calcium at rest?

A

Contain GluA2 subunits (R) that are calcium impermeable - this is RNA edited

45
Q

What are the 2 main ingestible excitotoxins?

A

Domoic acid

BMAA

46
Q

Summarise the abnormalities that can lead to excessive synaptic excitation?

A

Ingestion of excitotoxins (DA, BMAA)
Presynaptic anomalies; excessive triggering via AP, excessive release
Post synaptic anomalies; loss of cation selectivity (altered R/Q editing), changes in receptor, modulation of receptor number
Deficiencies in glutamate uptake

47
Q

What are the cellular mechanisms that can cause neuronal death?

A

Apoptosis

Necrosis

48
Q

Describe neuronal apoptosis?

A

Destruction of individual cells induced by a lack of physiological stimuli (lack of growth factors, hormonal changes)
NO INFLAMMATIO N
Shrinking of cytoplasm, condensation of nucleus
Blebbing of plasma membrane with no loss of integrity
Energy (ATP) - dependent active process
Cell death pathways

49
Q

Describe neuronal necrosis

A 
Affects GROUPS of cells 
Evoked by non-physiological events (virus, ischaemia, metabolic poisons) 
INFLAMMATION 
Swelling of cytoplasm and mitochondria 
Loss of plasma membrane integrity 
No energy required; passive process 
Calcium overload
50
Q

Chain of events in the cell death pathway - mild excitotoxic damage

A

Mild excitotoxicity allows NMDAR activation by ambient conc of glutamate
Increased mitochondrial calcium and free radical production
HOWEVER< there is preserved ATP generation (apoptosis is ATPdependent process)
Cytochrome C (Cytc), caspase 9, apoptosis inducing factor (AIF) released

51
Q

Chain of events in necrosis - severe excitotoxicity

A

Severe insults e.g. ischaemia, NMDAR activation is enhanced resulting in a large rise in intracellular calcium
This activated NOS (nitric oxide synthase) which increases mitochondrial calcium and superoxide generation
This allows the formation of peroxynitrite (ONOO-)
All of these chemicals result in cellular damage including DNA damage, and the activation of poly-ADP ribose polymerase (PARS)
Mitochondrial calcium accumulation and oxidative damage leads to the activation of permeability transition pore (PTP) which is linked to excitotoxic cell death

52
Q

What are the actions of peroxynitrite?

A

Protein oxidation
Lipid peroxidation
DNA/RNA oxidation

53
Q

What are the actions of PARS?

A

ATP depletion

NAD depletion

54
Q

What is the evidence to show than NMDAR is neuroprotective?

A

Blockade of NMDARs in vivo REDUCES neuronal viability postnatally
Elimination of NMDARs in vivo causes widespread apoptosis in developing neurons
In adult CNS, NMDAR blockage enhances neuronal loss

55
Q

What is the role of physiological NMDAR activity?

A

Neuronal survival
Synaptic plasticity - LTP
Neuronal development

56
Q

What curve do NMDAR show to glutamate?

A

Classical hormetic dose-response curve
Too much - pro death (excitotoxic)
Too little - neuronal cell death and lack of development

57
Q

Where are the NMDA receptors located that represent survival promotion?

A

Synaptic NMDARs

58
Q

Where are the NMDAARs located that promote death by chronically elevated glutamate levels?

A

Extra synaptic - linked to signalling pathways such as CREB function and mitochondrial depolarization
PRO-DEATH PATHWAYS

59
Q

What are the synaptic factors that result in good neuronal health e.g. neuroprotective factors?

A

Increased local mitochondrial function
Enhanced antioxidant defences
Enhanced trophic support
Suppressed apoptotic pathway

60
Q

How do NMDARs confer neuroprotective activity in connection with suppressed apoptotic activity?

A

Activate key signalling pathways such as P13 kinase which is a cell survival pathway

61
Q

What is PI3-kinase?

A

Pathway that phosphorylates PIP2 into PIP3 which is part of the phospholipase C signalling pathway
Can activate AkT
This is a cell surviving pathway

62
Q

How does Akt promote cell survival?

A

Inhibits activity GSK3-beta (inhibition of this kinase promotes neuronal survival)
Reduce level of BAD which has been linked to cell death. BAD can also reduce levels of Bcl-2 (Bcl-2 is a cell surviving protein)
Reduction in p53, which reduces levels of Bax. Bax is a cell death molecule and so the reduction enhances neuronal survival

63
Q

In summary, how does Akt promote cell survival?

A 
Reduced GSK30beta 
Reduced levels of BAD
Increased Bcl-2
Reduced p53
Reduced Bax
64
Q

In terms of gene expression, what is the role of NMDARs?

A

NMDAR synaptic activity can induce the expression of pro-survival genes but supresses pro-death genes

65
Q

How does NMDAR induce the expression of pro-survival genes?

A

Calcium influx in the cell allows nuclear calcium signalling which can target CREB genes
NMDAR receptors allows communication between the synapse and the nucleus via calcium transport

66
Q

Which CREB target genes are implicated in NMDAR dependent neuroprotection?

A

AID; Activity-dependent Inhibitors of Death

NFAT; Nuclear Factor of Activated T cells - a calcium responsive transcription factor

67
Q

What is the role of AID and NFAT genes?

A

Activation of these genes has been visible to show neuroprotective effects in vivo and in vitro

68
Q

Why does oxidative damage occur in cells?

A

Imbalance in ROS (reactive oxygen species) production and the cells capacity to neutralize ROS
Correct redox regulation is essential in all cells

69
Q

What is the role of NMDAR in the oxidative stress of neurones?

A

The vulnerability of neurones to oxidative death is regulated by synaptic NMDAR activity
Neurones with a high NMDAR activity withstand oxidative damage more readily that electrically quiet neurones
Neurones are highly vulnerable to oxidative damage after NMDAR blockade in vivo and in vitro

70
Q

How does NMDAR activity boost antioxidant mechanisms of cells?

A

Synaptic activity exerts changes in the thioredoxin-peroxiredoxin system
Synaptic activity also promotes a series of gene expression changes that boost anti-oxidant defences

71
Q

What is the role of the thioredoxin-peroxiredoxin system?

A

Enhanced thioredoxin activity will facilitate the reduction of hyperoxidized peroxiredoxins (antioxidant enzyme)

72
Q

What are the changes that can occur to gene transcription that confer an antioxidant boost in NMDAR synapses?

A

Triggers transcriptional suppression of an inhibitor TXNIP (FOXO target gene)
This ultimately boosts anti-oxidant defences

73
Q

What is the main role of mitochondria in neuronal health?

A 
Energy demands (ATP) 
Calcium homeostasis
74
Q

What is the role of neuronal activity on mitochondrial function?

A

Regulated mitochondrial fission/fusion and intracellular trafficking
This balances energy demands with localised availability

75
Q

In summary, what is the role of synaptic activity on mitochondrial action?

A

Enhances mitochondrial fission
Reduced mitochondrial mobility
Localises mitochondria to dendritic spines

76
Q

How does synaptic activity regulate neurotrophic factors?

A

Elevates expression of BDNF which contributes to neuroprotection
Releases and matures pro-NGF (nerve growth factor) activity
Upregulates FGF2 which has shown to delay photoreceptor death

77
Q

In terms of NMDAR mediated cell death, describe the role of mitochondrial dysfunction

A

Mitochondrial dysfunction due to excessive calcium uptake is key for severe excitotoxicity

78
Q

Describe how mitochondria uptake excessive calcium which ultimately leads to dysfunction in NMDAR mediated excitotoxicity

A

Mitochondrial membrane is depolarized by calcium uptake which inhibits ATP production - this can deplete cytosolic ATP due to reversal of mitochondrial ATPase
Loss of ATP decreases the ability of neurons to regulate calcium
Mitochondrial calcium uptake also promotes production of ROS which further damages the mitochondria

79
Q

What mediates calcium efflux in neurons?

A

PMCA and NCX
Plasma membrane calcium ATPase
Na/Ca exchanger

80
Q

What are calpains?

A

Calcium dependent proteases

81
Q

What is the role of calpain in NMDAR mediated cell death?

A

Cleaves the major NCX3 isoform which impairs its function
Inactivates PMCA following excitotoxic insults
Impairs the efflux of calcium
THEREFORE
Excessive calcium influx IMPAIRS calcium efflux mechanisms

82
Q

What are SAPKs?

A

Stress activated protein kinases

83
Q

Which SAPKs are implicated in NMDAR driven cell death?

A

P38 MAPK and JNK

In cerebellar and cortical neurons, NMDAR dependent p38 MAPK activation involves nNOS (neuronal nitric oxide synthase)

84
Q

What determines if NMDAR activity is neuroprotective or excitotoxic?

A

Stimulus intensity
Distribution (locus) of NMDAR - synaptic or extra synaptic
Molecular density/ subunit composition of NMDAR

85
Q

What is the evidence that the intensity of the stimulus to NMDAR is key in whether they act in a neuroprotective manner or excitotoxic?

A

Modest/ physiological NMDAR activity promotes neuroprotection
Too much or too little = cell death = hormetic dose response curve
Pro survival requires lower calcium levels than pro death

86
Q

What is the significance of NMDAR locus (synaptic or extrasynaptic) in whether they play a role as neuroprotective or excitotoxic?

A

Synaptic locus; calcium influx well tolerated. Activated ERK pathway. Activated CREB gene expression (AIB, NFAT). Activated pro-survival P13-kinase/ Akt pathway

Extrasynaptic; calcium influx triggers cell death/ Induces ERK inactivation. CREB dephosphorylation. No activation of PI3-kinase/ Akt

87
Q

What is the significance of the NMDAR subunit composition that differentiates their functional ability (pro survival or pro death)?

A

Evidence isn’t clear
One study: NR2B promotes neuronal death but NR2A promotes survival
BUT NR2A can promote excitotoxicity and NR2B can mediate pro-survival signalling

88
Q

What is the composition of NMDARs?

A

NR1, NR2 (NR2A/B/C/D) +/- NR3

89
Q

What do the NR2 subunits of NMDARs determine?

A

Biophysics and pharmacology

90
Q

In the hippocampus, which NMDAR subunits predomimnate?

A

NR2A and NR2B

91
Q

What is the difference between NR2A and NR2B?

A

NR2A: synaptic
NR2B: extra-synaptic

92
Q

Can NMDARs be targeted therapeutically?

A

Animal studies implicate NMDARs in ischaemic damage but NMDAR antagonists for stroke failed due to poor tolerance and efficacy

93
Q

Describe memantine

A

NMDAR antagonist that blocks chronic NMDAR activity

94
Q

Describe the role of NMDA in AD?

A

Synaptic NMDA activation:
Reduces A-beta production and release
Reduces intraneuronal Ab
Increases components of non-amyloidogenic pathway (soluble APP alpha)
Recruits putative a-secretase ADAM-10
THEREFORE; synaptic NMDA receptors have protective factors against amyloid factors in AD

95
Q

What is the role of NMDA in SMA and ALS?

A

Degeneration of motor neurones
SMA-like mice; daily NMDA in vivo can reduce motor neuron death and improve motor behaviour and lifespan
ALS mouse model; significant decrease in NR2A subunit identified with coincident alterations in synaptic plasticity and dendritic outgrowth

96
Q

What is the role of NMDA in HD?

A

Synaptic activity increases the non-toxic mutant huntingtin inclusions via NMDAR
YAC 128 HD mouse model; increased extrasynaptic NMDAR expression (increase in pro-death)

97
Q

Is there a role for memantine in HD?

A

Memantine which preferentially targets extrasynaptic NMDAR improves neuropathological behaviour in HD mouse models

BMSc - Neuropharmacology and Behaviour (27 decks)

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