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Applied Neuroanatomy > Excitotoxicity > Flashcards

Excitotoxicity Flashcards

1
Q

What is excitotoxicity?

A

cell death resulting from the toxic actions of excitatory amino acids

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2
Q

What is the main excitatory neurotransmitter in the brain?

A

Glutamate

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3
Q

What sort of processes is Glutamate essential for?

A

LTP and neurodevelopment

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4
Q

What are some other excitotoxicity causative amino acids?

A

cysteine, cysteine sulfonate, cysteic acid and aspartate

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5
Q

Why does glutamate not cause endogenous toxicity?

A

because the levels are too low

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6
Q

What removes glutamate from the EC space?

A

ATP-dependent glutamate transporters

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7
Q

How is cytosolic glutamate transported into vesicles?

A

vesicular ATP-dependent glutamate transporters

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8
Q

What can happen to glutamate uptake during an ischemic attack?

A

uptake can stop and reverse causing glutamate to spill out into the EC space or cytoplasm

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9
Q

What is the influence of glutamate on the post-synaptic neuron?

A

influx of Na

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10
Q

Which receptors does glutamate activate on the post-synaptic neuron?

A

mGluRs
AMPA
NMDA
Kainate

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11
Q

Why do NMDA receptors play a key role in glutamate excitation?

A

NMDAs are highly permeable to calcium
Pathological activation of NMDAs are associated with neuronal death in ischemia
NMDA R excessive activation associated with neurodegeneration

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12
Q

What are the components of the hippocampal EPSC?

A

Fast AMPA activation

Slow NMDA activation

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13
Q

What sort of malfunctions may occur at the glutamatergic synapse?

A

excessive or deficient

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14
Q

What is domoic acid (DA)?

A

a glutamate analogue associated with harmful algal blooms

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15
Q

What is amnesic shellfish poisoning?

A

where high concentrations of DA have accumulated in shell fish - causes short term memory loss, brain damage and in severe cases, death in mammals

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16
Q

What does amnesic shellfish poisoning do in mammals?

A

cause STM loss, brain damage and potentially death

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17
Q

How does DA exert its effects?

A

activates non-NMDA receptors which increases IC Ca which promotes the release of glutamate
-this then promotes further release of glutamate through NMDAs

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18
Q

Why is DA so toxic?

A

it is not readily removed by glutamate transporters

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19
Q

What does BMAA stand for?

A

B-Methylamino-L-Alanine

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20
Q

What is BMAA?

A

a neurotoxin produced by cyanobacteria which could be considered the cause of ALS or parkinsonism-dementia complex

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21
Q

What can BMAA be considered the cause of?

A

ALS or Parkinsonism dementia

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22
Q

How does BMAA act as a neurotoxin?

A

kills motor neurons by activating AMPA/Kainate glutamate receptors and boosting production of ROS

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23
Q

How high can EC glutamate rise to during ischemia?

A

100uM

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24
Q

What reduces ischemic neuronal damage in vivo?

A

NMDAR antagonists

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25
Q

What are the potential pre-synaptic abnormalities that can lead to excessive excitation?

A
  1. AP increased frequenct
  2. Ca influx - altered voltage-dependence/spontaneous activation of VGCC
  3. Glutamate release: altered requirement for Ca influx/altered fusion/altered vesicle loading
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26
Q

What is toxicity commonly due to?

A

lack of ability to remove glutamate

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27
Q

What is glutamate toxicity enhanced by?

A

reversal of uptake by plasma membrane glutamate transporters

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28
Q

Why might plasma membrane glutamate transporters reverse their uptake?

A

due to cytosolic ATP depletion

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29
Q

What are the potential post-synaptic abnormalities that can lead to excessive excitation?

A
  1. increased affinity of the glutamate binding site (not common)
  2. increased density of glutamate receptors
  3. deficient cation selectivity of the ionophore (R/Q editing)
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30
Q

Under what conditions do AMPA Rs become permeable to Ca?

A

When RNA editing fails and GluA(Q)2 channels are formed instead of GluA(R)2

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31
Q

What are the mechanisms of neuronal death?

A

Apoptosis
Shrinking of the cytoplasm and condensation of the nucleus
Necrosis

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32
Q

Describe apoptosis

A

destroys individual cells

induced by physiological stimuli

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33
Q

What sort of physiological stimuli may induce apoptosis?

A

lack of growth factors

hormonal changes

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34
Q

Describe what happens when the cytoplasm shrinks and the nucleus condenses?

A

blebbing of the plasma membrane - no integrity

energy dependent active process using cell death pathways

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35
Q

Describe necrosis

A

affects groups of cells
evoked by non-physiological events
inflammation
swelling of the cytoplasm and the mitochondria
no energy requirement, passive process by Ca overload

36
Q

What are the non-physiological events that may lead to necrosis?

A

virsuses, ischemia, poisons

37
Q

Why is there no energy requirement for necrosis?

A

the process is passive via Ca overload

38
Q

Describe the process of apoptosis

A
  • mild excitotoxic insults allow NMDAR activation by ambient conc. of glutamate
  • leads to increased mitochondrial Ca and ROS production (still relatively preserved ATP production)
  • the mitochondria may then release cytochrome c, caspase 9 or apoptosis inducing factor
39
Q

What factors may mitochondria produce to initiate apoptosis?

A

caspase 9, cytochrome c or apoptosis inducing factor

40
Q

Describe the process of necrosis

A
  • severe insult leads to enhanced NMDAR activation which leads to increased IC Ca levels
  • this activates NOS which increases mitochondrial Ca and superoxide generation and formation of peroxynitrite (ONOO-)
  • results in cellular damage including DNA damage leading to activation of poly-ADP-ribose polymerase (PARS)
  • mitochondrial Ca accumulation and oxidative damage lead to activation of the permeability transition pore (PTP) that is linked to excitotoxic cell death
41
Q

Why are NMDA Rs considered essential?

A

when blockaded or KO there is apoptosis of neurons and the viability of neurons is reduced

42
Q

Which NMDA Rs promote survival?

A

synaptic NMDAR

43
Q

What happens when EC glutamate levels are chronically elevated?

A

Extra-synaptic NMDA Rs are activated which is coupled to pro-death signalling

44
Q

How do extrasynaptic NMDA Rs signal for cell death?

A

shut down CREB signalling and triggers mitochondrial depolarisation

45
Q

Can synaptic NMDA Rs contribute to cell death?

A

Yes but not as efficiently

46
Q

What are the neuroprotective mechanisms of glutamergic signalling?

A

Suppressed apoptotic pathway

Enhanced Antioxidant Defences

47
Q

What mechanisms suppress the apoptotic pathway?

A

reduction in p53
PI3K cascade
expression of survival genes i.e CREB pathway

48
Q

In what way does PI3K cascade suppress apoptosis?

A

Activating Akt

49
Q

What does Akt influence?

A

suppression of p53 -> decrease in Bax
suppression of GSKb
suppression of BAD -> decrease in Bcl2

50
Q

What does suppression of p53 result in?

A

decrease in Bax

51
Q

What does suppression of BAD result in?

A

decreased in Bcl 2

52
Q

What CREB target genes are activated to suppress apoptosis?

A

AID - activity-dependent inhibitors of death

NFAT - nuclear factor of Activated T cells

53
Q

What is significant about NFAT?

A

It is a Ca responsive TF

54
Q

What does Ca influx via NMDARs enable?

A

communication between the synapse and the nucleus -> CREB

55
Q

Why is NMDAR activation important in antioxidant defences?

A

neuronal vulnerability to oxidative damage is regulated by synaptic NMDAR activity

56
Q

What are the key mechanisms involved in boosting anti-oxidant defences?

A

thioredoxin-peroxiredoxin system

gene expression changes

57
Q

What happens in the thioredoxin-peroxiredoxin system?

A

enhanced thioredoxin activity -> reduction of hyperoxidised peroxiredoxins

58
Q

What are peroxiredoxins?

A

antioxidant enzymes

59
Q

What gene expression changes that boost anti-oxidant defences?

A

suppression of thioredoxin inhibitior - TXNIP

60
Q

What is TXNIP?

A

A FOXO target gene - a thioredoxin inhibitor

61
Q

What key elements for neuronal health are regulated by mitochondria?

A

Ca homeostasis and energy demands

62
Q

What does neuronal activity regulate in terms of mitochondria?

A

mitochondrial fission
reduced mitochondrial mobility
localisation of mitochondria to dendritic spines

63
Q

What is mitochondrial fission?

A

the ability of mitochondrial cells to divide

64
Q

How does synaptic activity enhance neuroprotective mechanisms?

A

regulating the expression and release of neurotrophic factors

65
Q

What examples of neurotrophic factors may synaptic activity activate?

A

BDNF
pro-NGF
upregulation of FGF2

66
Q

What does excessive Ca uptake do to mitochondria?

A

causes depolarisation of the mitochondrial membrane which inhibits ATP production

67
Q

What does mitochondrial dysfunction result in?

A

inability of neurons to regulate Ca

ROS production

68
Q

What pathways may be activated in NMDAR mediated cell death?

A

mitochondrial dysfunction
calpain activation
Stress activated protein kinases

69
Q

What is the result of excessive Ca uptake in the neuron?

A

impairs Ca efflux mechanisms

70
Q

What is normally responsible for Ca efflux under regular conditions?

A

plasma membrane Ca-ATPase (PMCAs)

NCX3

71
Q

How does excessive Ca uptake affect calcium efflux?

A

calpains are activated and cleave the major NCX3 isoform and may also inactivated PMCAs

72
Q

What is the effect of calpain activation?

A

cleavage of major NCX3 isoform

inactivation of PMCAs

73
Q

What are the Stress Activated Protein Kinases activated?

A

p38 MAPK and JAK

74
Q

What does p38 MAPK activation involve in cerebellar and cortical neurons?

A

nNOS

75
Q

What determines in NMDAR activity is neuroprotective or excitotoxic?

A

stimulus intensity
NMDAR locus
NMDAR subunit composition

76
Q

What are the differential effects of stimulus intensity?

A

Too much or too little causes cell death pathways

77
Q

What are the pathways are activated by synaptic NMDARs?

A

ERK pathways
CREB-dependent gene expression
PI3K-Akt pathways

78
Q

What are the pathways activated by extrasynaptic NMDARs?

A

ERK inactivation
CREB dephosphorylation
no activation of PI3K-Akt

79
Q

What are the general NMDAR subunit compositions?

A

one NR1, one or NR2 subunits (A/B/C/D) with or without an NR3

80
Q

What is the importance NR2 subunits?

A

determine biophysics and pharmacology of the cell

81
Q

Which NMDAR subunits dominate in the hippocampus?

A

NR2A (synaptic) and NR2B (Extra-Synaptic)

82
Q

What is the significance of NMDARs in AD?

A

synaptic activation reduces Ab production and release and increases the components of non-amylodogenic pathway APPa

83
Q

What is the significance of NMDARs in SMA?

A

administration of NMDA daily prevents MN death and improves life span and motor behaviour

84
Q

What is the significance of NMDARs in ALS?

A

ALS mouse model has decreased NR2A subunits which is coincident with alterations in synaptic plasticity

85
Q

What is the significance of NMDARs in HD?

A

synaptic activity increases non-toxic mutant huntington inclusions
YAC-128 mouse has increased extrasynaptic NMDARs leading to pro death signalling
memantine improves neuropathology and behaviour

Applied Neuroanatomy (11 decks)

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