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BS42023- Applied Neuroanatomy & Neurodegenerative Disorders > BS42023 L1 > Flashcards

BS42023 L1 Flashcards

1
Q

What is Excitotoxicity?

A

cell death resulting from the toxic actions of excitatory amino acids

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2
Q

amino acids that cause excitotoxicity include (6)

A
  1. cystine
  2. cystine sulfonate
  3. cysteic acid
  4. homocysteine
  5. glutamate
  6. aspartate
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3
Q

What is the most neurotoxic neurotransmitter and why?

A

glutamate- low concentrations of this applied to neurons over long periods of time can kill them.

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4
Q

What are the implications of excitotoxicity? (7)

A
  1. Brain trauma
  2. Heavy Metal Toxicity
  3. Brain tumours
  4. neurodegenerative disorders
  5. CNS infections
  6. autoimmune disorders
  7. stroke
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5
Q

What is the most effective way for glutamate reuptake?

A

glial transporter

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6
Q

what are the key structures on the pre-synapse of a glutamatergic synapse? (3)

A
  • Na+/ K+/ Ca2+ channels
  • vesicles
  • ATP-dependent glutamate transporters
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7
Q

what are the key structures on the post-synapse of a glutamatergic synapse? (2)

A
  • ionotropic glutamate receptors (Kainate, AMPA, NMDA)

- metabotropic glutamate receptors

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8
Q

How is glutamate released from the pre-synaptic terminal?

A

action potential fires down to the axon terminal -> Ca2+v channels open and influx of Ca2+ -> triggers neurotransmitter release from vesicles

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9
Q

are extracellular glutamate levels high or low?

A

low

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10
Q

what happens to glutamate uptake during ischaemic attack?

A

it stops or reverses

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11
Q

How do NMDARs induce excitotoxicity?

A

by chronic/pathological activation- this causes prolonged glutamate release which is toxic when in high concentrations in extracellular environment.

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12
Q

what is domoic acid?

A

a glutamate analogue associated with algal blooms (it is neurotoxic)

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13
Q

what is the mechanism of action of domoic acid?

A

it is a very potent agonist of non-NMDA receptors (KA/AMPA)

DA activation of KA/AMPA receptors increases intracellular Ca2+ which promotes release of glutamate.

This activates NMDARs which results in even more glutamate release.

DA is not readily removed from the synapse and so remains which is why it is extremely neurotoxic as it continues to activate the receptors.

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14
Q

how does b-methylamino-L-alanine (BMAA) kill motor neurons?

A

by activating KA/AMPA receptors and promoting production of oxygen radicals

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15
Q

what is the concentration of extracellular glutamate during ischaemia?

A

100mM from 1uM

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16
Q

what is the main cause of glutamate toxicity in vivo?

A

NMDARs

17
Q

what are some abnormalities that can occur on the pre-synaptic terminal to cause excess glutamate release? (3)

A
  1. increased action potential firing
  2. altered voltage dependence/activation of VGCC
  3. altered requirement for calcium influx/ altered fusion/ altered vesicle loading with transmitter
18
Q

what are some abnormalities that can occur on the post-synaptic terminal to cause excess glutamate release? (4)

A
  1. increased affinity of the glutamate binding site
  2. increased density of glutamate receptor
  3. deficient cation selectivity of the ionophore
  4. abnormal (positive) modulation of GluR function
19
Q

what can happen to AMPARs if RNA editing fails?

A

they can become permeable to Ca2+ as well as Na+.

20
Q

what does excessive calcium influx via NMDARs contribute to? (2)

A

apoptosis and necrosis

21
Q

how do NMDARs contribute to apoptosis?

A
  • NMDAR activation leads to an increase in mitochondrial Ca2+ and free radical production
  • the mitochondria then releases cytochrome c, caspase 9, apoptosis-inducing factor and other mediators that lead to apoptosis.
22
Q

how do NMDARs contribute to necrosis?

A
  • activation of NMDARs increases intracellular Ca2+ levels.
  • this activated NOS which increases mitochondrial Ca2+ and superoxide generation
  • this then forms peroxinitrite (ONOO-)
  • this leads to cellular damage including DNA damage; activates PARS
  • Mitochondrial Ca2+ accumulation and oxidative damage lead to activation of the permeability transition pore (PTP) that is linked to excitotoxic cell death.
23
Q

how is localisation of NMDARs important?

A

pathologically low levels of synaptic NMDAR activity and pathologically high levels of extrasynaptic NMDAR activity pro-death signalling pathways are activated

24
Q

how do synaptic NMDARs promote cell survival? (4)

A
  • suppressed apoptotic pathway
  • enhanced trophic support
  • enhanced antioxidant defences
  • increased local mitochondrial function
25
Q

what are examples of anti-apoptotic pathways induced by NMDAR activation? (3)

A
  • CREB target gene expression
  • Akt
  • p53
26
Q

how does Akt promote survival?

A

Akt can inhibit a number of pathways linked to cancer and things like diabetes. eg. GSK3b, BAD (–> Bcl2 which is a key apoptotic marker), p53 (–> Bax which is a key marker of cancer promoting pathways)

27
Q

what groups of genes are activated by CREB following NMDAR neuroprotection? (2)

A
  • AIB; Activity-dependent Inhibitors of Death

- NFAT; Nuclear Factor of Activated T cells

27
Q

what are the key mechanisms for boosting antioxidant defences? (2)

A
  • Synaptic activity exerts changes in the thioredoxin-peroxiredoxin system. e.g. enhanced thioredoxin activity. This facilitates reduction of hyperoxidized peroxiredoxin (antioxidant enzymes).
  • Synaptic activity also promotes a series of gene-expression changes that boost anti-oxidant defences. E.g. triggers transcriptional suppression of the thioredoxin inhibitor, TXNIP (a FOXO target gene). This boosts anti-oxidant defences.
28
Q

how does synaptic activity regulate mitochondrial function?

A

it enhances mitochondrial fission, reduces mitochondrial mobility, localises mitochondria to dendritic spines.

29
Q

how does synaptic activity enhance trophic support?

A
  • Synaptic activity regulates the expression and release of many neurotrophic factors that have neuroprotective actions.
  • For example; synaptic activity elevates expression of BDNF which contributes to neuroprotection. The release and maturation of pro-NGF is activity-dependent. In vivo electrical stimulation upregulates FGF2 and delays photoreceptor death.
30
Q

name three ways in which NMDAR activation can induce cell death

A
  • mitochondrial dysfunction
  • calpain activation
  • stress activated protein kinases
31
Q

What determines if NMDAR activity is neuroprotective or excitotoxic?

A
  • Stimulus intensity
  • NMDAR locus
  • NMDAR subunit composition.

BS42023- Applied Neuroanatomy & Neurodegenerative Disorders (6 decks)

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