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Neuroanatomy and neurodegenerative disorders > Excitotoxicity > Flashcards

Excitotoxicity Flashcards

1
Q

What is the main excitatory neurotransmitter in the brain?

A

Glutamate

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2
Q

What is excitotoxicity?

A

Cell death resulting from the toxic actions of excitatory amino acids e.g. glutamate

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3
Q

Name some examples of amino acids that would cause excitotoxicity

A

Cysteine, cysteic acid, cysteine sulfonate, homocysteine, glutamate and aspartate

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4
Q

Which neurotransmitter is the most abundant in the CNS and the most neurotoxic?

A

Glutamate Even low levels of glutamate applied to neurons can kill the cells Oral glutamate produces neurodegeneration in vivo e.g. monosodium glutamate in Chinese food

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5
Q

What are some of the potential implications of excitotoxicity?

A

Stroke, brain trauma, heavy metal toxicity, brain tumours, CNS infections, neurodegenerative diseases, autoimmune disorders - all of these are linked to high levels of glutamate

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6
Q

Describe the steps that occur in the presynaptic neuron during synaptic transmission

A

Neurotransmitter (NT) is synthesised (1+2) and stored in vesicles (3+4) in the presynaptic terminal. AP propagates along the axon and depolarises the presynaptic terminal (5). Calcium influx occurs in response to depolarisation (6) which causes release of the NT via exocytosis (7).

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7
Q

Describe the steps that occur in the postsynaptic neuron during synaptic transmission

A

After the NT is released via exocytosis it diffuses to the postsynaptic membrane (8) and interacts with the postsynaptic receptors (9). Inactivation of NT (10) by reuptake of NT into nerve terminal (11) and glial cells (12). Interaction with presynaptic receptors (13)

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8
Q

What are the 2 mechanisms by which glutamate is removed to avoid toxicity?

A
  1. Glutamate reuptake into presynaptic terminal via transporter
  2. Uptake into glial cells (main route)
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9
Q

What happens along the axon that allows voltage gated calcium channels on the presynaptic terminal to open?

A
  • Action potential fires on the axon -> voltage gated Na channels open and Na floods in -> depolarisation of the membrane
  • Delayed opening of K channels causes K to flood out which repolarises the membrane.
  • This cycle moves along the axons to the presynaptic terminals where voltage-gated calcium channels open -> calcium influx -> triggers neurotransmitter release
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10
Q

How are extracellular levels of glutamate kept low to avoid endogenous toxicity?

A
  • ATP-dependent glutamate transporters on the plasma membrane remove glutamate from the extracellular space.
  • This cytosolic glutamate is then transported into vesicles by vesicular ATP-dependent glutamate transporters
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11
Q

When can glutamate uptake stop or even reverse?

A

Glutamate uptake can stop or reverse (ie. glutamate spills out of the cell) during metabolic compromise e.g. during ischaemic attack

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12
Q

What is the relationship between NMDA receptors and calcium?

A

NMDA receptors are highly permeable to calcium and thus NMDAr activation allows calcium entry

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13
Q

What ion can block NMDA receptors in a voltage dependent manner?

A

Magnesium ions

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14
Q

Activation of NMDA receptors requires glutamate as well as what other neurotransmitter?

A

Glycine

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15
Q

What must occur to relieve the block that magnesium puts on NMDA receptors?

A
  • Sufficient depolarisation must occur.
  • When the cell is normally polarised, physiological levels of Mg cause block to the NMDAr so the cell must be depolarised for the block to be relieved
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16
Q

Why do NMDArs not contribute to basal synaptic transmission?

A

This is because when the cell is normally polarised Mg blocks it from opening

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17
Q

What happens to NMDA receptors during intense synaptic activity?

A
  • AMPArs are activated and sufficient depolarisation occurs to alleviate the Mg block of NMDArs.
  • AMPArs are associated with fast synaptic transmission in the CNS whereas NMDArs contribute a slow component to the excitatory synaptic potential
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18
Q

NMDArs mediate excitotoxicity due to their high calcium permeability and incomplete desensitisation. What can happen when NMDArs are pathologically activated?

A
  • Neuronal death can occur after acute excitotoxic trauma e.g. ischaemia
  • Chronic neurodegenerative diseases are also associated with excessive NMDAr activation
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19
Q

What are possible malfunctions of the glutamatergic synapse?

A

Excessive excitation (excitotoxicity) OR deficient excitation

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20
Q

Where can domoic acid be found in the environment?

A

Certain harmful algal blooms, plankton feeders e.g. shellfish, associated with amnesic shellfish poisoning (ASP)

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21
Q

What does domoic acid do in mammals?

A

Acts as a neurotoxin, causing short-term memory loss, brain damage and sometimes even death

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22
Q

Name the three types of ionotropic glutamate receptors

A

NMDA, AMPA and kainate

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23
Q

Domoic acid is an agonist for what kind of receptor(s)?

A

Non-NMDA receptors i.e. kainate and AMPA receptors

24
Q

Explain the mechanism by which domoic acid promotes glutamate release

A
  • Domoic acid activates AMPA/KA receptors which increases the levels of intracellular calcium and promotes release of glutamate.
  • This released glutamate then activates NMDARs which promotes even more glutamate release
25
Q

What makes domoic acid very toxic?

A
  • It is not readily removed by glutamate and is therefore very toxic.
  • It is also up to 20-fold more potent than kainate at kainate receptors
26
Q

Domoic acid can cause neuronal necrosis, which areas of the brain does this most commonly occur?

A

Hippocampus and amygdala

27
Q

What is beta-methylamino-L-alanine (BMAA)?

A

A neurotoxin produced by cyanobacteria

28
Q

What species of animal consumes Cycaad seeds and why can this be dangerous?

A
  • Cycaad seeds contain BMAA.
  • Fruit bats consume these and then the Chamarro people eat the fruit bats thus exposing themselves to the harmful effects of BMAA
29
Q

What is BMAA considered the cause of?

A

Amyotrophic lateral sclerosis (ALS)/parkinsonism-dementia complex

30
Q

How does BMAA kill motor neurons?

A

By activating AMPA-kainate glutamate receptors and boosting production of free radicals

31
Q

Extracellular glutamate levels can increase up to 100uM during ischaemia. What class of drug might be able to reduce ischaemic neuronal damage?

A

NMDAR antagonists - glutamate toxicity is predominantly via NMDARs so blocking these could prevent ischaemic damage to neurons

32
Q

What presynaptic anomalies may occur and lead to excessive excitation?

A
  1. Increased firing of APs
  2. Calcium influx - voltage gated calcium channels could spontaneously open regardless of the membrane potential
  3. Glutamate uptake failure or altered fusion of the vesicle
  4. Reversed uptake (release) by plasma membrane glutamate transporters (due to cytosolic ATP depletion)
33
Q

What postsynaptic anomalies may occur and lead to excessive excitation?

A
  • Increased affinity of the glutamate binding site
  • Increased density of glutamate receptors
  • Deficient cation selectivity of the ionophore
34
Q

What happens to AMPArs if RNA editing fails?

A

AMPARs usually contain GluA2 subunits that are calcium impermeable however if RNA editing fails, calcium permeable GluA2 containing receptors are formed

35
Q

What is apoptosis and what causes it to happen?

A
  • Cell death induced by physiological stimuli.
  • Involves shrinking of the cytoplasm, condensation of the nucleus and blebbing of the plasma membrane (no loss of integrity)
36
Q

What is necrosis and what causes it to happen?

A
  • Death of groups of cells evoked by non-physiological events e.g. viruses, ischaemia
  • Inflammation occurs via swelling of the cytoplasm and mitochondria.
  • The plasma membrane loses its integrity
  • There is calcium overload associated with necrosis
37
Q

Apoptosis is a passive process and necrosis is an active process. True or false?

A

False - apoptosis is an ATP dependent process whereas necrosis is passive

38
Q

What is the role of NMDAr activation in apoptosis?

A
  • Mild excitotoxic insult allows NMDAR activation by ambient concentrations of glutamate.
  • This leads to increased mitochondrial calcium and free radical production.
  • The mitochondria may then release Cytc, caspase 9, apoptosis inducing factor and other mediators, leading to apoptosis
39
Q

After severe insults e.g. ischaemia, NMDAR activation is enhanced resulting in increased intracellular calcium. What then happens as a result of this?

A
  • Activates nitric oxide synthase -> increases mitochondrial calcium and superoxide generation -> formation of peroxynitrite -> cellular damage (inc. DNA damage) -> activation of PARS.
  • Mitochondrial calcium build up and oxidative damage lead to activation of the permeability transition pore that is linked to excitotoxic death
40
Q

How does NMDAR activation move from being neuroprotective to neurotoxic?

A
  • NMDARs can be neuroprotective but if overstimulated can become neurotoxic
  • Pro-survival actions are mediated by synaptic NDMARs but when extracellular glutamate levels are chronically elevated, extrasynaptic NMDAR activation is coupled to pro-death signalling
41
Q

What is the role of PI3-kinase and Akt in neuroprotection?

A
  • The PI3-kinase/Akt pathway is activated by NMDARs in many neurons.
  • Akt targets GSK3B, BAD and p53 to promote neuronal survival.
42
Q

What does synaptic activity do to protect the neuron?

A
  • It induces expression of survival genes and suppresses pro-death genes.
  • Calcium influx via NMDARs enable communication between the synapse and the nucleus allowing resistance to apoptotic and excitotoxic insults
43
Q

Name 2 examples of CREB target genes that have been implicated in NMDAR dependent neuroprotection

A
  • AID - activity dependent inhibitors of death
  • NFAT - nuclear factor of activated T cells
44
Q

When does oxidative damage occur in the neuron?

A
  • When there is an imbalance in reactive oxygen species (ROS) production and cells capacity to neutralise ROS
  • Neurons are highly vulnerable to oxidative damage after NMDAR blockade as NMDAR activity regulates oxidative death of neurons
45
Q

What are some of the key mechanisms of boosting antioxidant defences?

A
  • Synaptic activity exerts changes in the thioredoxin-peroxiredoxin system - enhanced thiredoxin activity allows reduction of antioxidant enzymes
  • Synaptic activity also promotes a series of gene expression changes that boost anti-oxidant defences
46
Q

In what ways do synaptic activity regulate mitochondrial function?

A
  • Enhances mitochondrial fission
  • Reduces mitochondrial mobility
  • Localises mitochondria to dendritic spines
47
Q

Synaptic activity regulates the expression and release of many neurotrophic factors that have neuroprotecive actions. Name some examples of these neurotrophic factors

A

Synaptic activity causes:

  • Increased expression of BDNF which is neuroprotective
  • Release and maturation of pro-NGF
  • Upregulates FGF2 and delays photoreceptor death
48
Q

What role does mitochondrial dysfunction play in excitotoxicity?

A
  • Excessive calcium uptake by mitochondria causes the mitochondrial membrane to depolarise which inhibits ATP production.
  • Loss of ATP means the ability of neurons to regulate intracellular calcium decreases leading to severe excitotoxicity.
  • Mitochondrial calcium uptake also promotes ROS production causing further mitochondrial damage
49
Q

How are calpains activated and what do they cause?

A
  • Calpains are activated by excessive NMDAR calcium influx.
  • Calpains cleave the major sodium, calcium exchanger (NCX3), impairing its function.
  • They also play a role in inactivating plasma membrane calcium ATPase (PMCA) following excitotoxic insults
50
Q

What is another substance that is implicated in NMDAR driven cell death (other than calpains and mitochondrial dysfunction)?

A

Stress activated protein kinases (SAPK)

51
Q

What determines if NMDAR activity is neuroprotective or excitotoxic?

A
  • Stimulus intensity - too little or too much NMDAR activity promotes cell death
  • NMDAR locus
  • NMDAR subunit composition
52
Q

Why is the NMDAR locus important when determining neuroprotective or excitotoxic effects?

A
  • Synaptic and extra-synaptic sites signal differently.
  • Synaptic - calcium influx is well tolerated by cells, activates the ERK pathway and CREB-dependent gene expression which activates the pro-survival PI3-kinase/Akt pathway
  • Extrasynaptic - calcium influx triggers cell death via ERK inactivation, CREB dephosphorylation and no activation of the PI3/Akt pathway.
53
Q

Why is the NMDAR subunit important when determining neuroprotective or excitotoxic effects?

A

It is hypothesised that NR2 subunits influence NMDARs signal for either death or survival

54
Q

What is an example of an NMDAR antagonist and what is its mechanism?

A

Memantine - blocks chronic NMDAR activity (i.e. pathological activity) without altering normal synaptic function

55
Q

What are the effects of using an NMDAR antagonist in Alzheimer’s?

A
  • Memantine binding to the NMDA receptor with a higher affinity than Mg2+ ions, means it is able to inhibit the prolonged influx of Ca2+ ions associated with excitotoxicity.
  • Synaptic NMDAR activation:
    • Reduces amyloid beta production and release
    • Reduces intraneuronal amyloid beta Increases components of non-amyloidogenic pathway
    • Recruits putative alpha-secretase ADAM-10
    • Thus overall synaptic NMDAR activity promotes amyloidogenic processing
56
Q

In what conditions could administration of NMDA be beneficial?

A

SMA (spinal muscular atrophy) and ALS (amyotrophic lateral sclerosis) as it has been shown to decrease motor neuron death, improve motor function and lifespan in vivo

57
Q

In what other condition has memantine proven to be beneficical?

A

Huntington’s disease - low doses of memantine (which preferentially blocks extrasynaptic NMDAR) improves neuropathology and behaviour in mouse models

Neuroanatomy and neurodegenerative disorders (7 decks)

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