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Neuro I > Excitotoxicity > Flashcards

Excitotoxicity Flashcards

0
Q

Excitatory amino acids

A

Glutamate (mostly)

Aspartate (often found with glutamate)

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1
Q

2 things that play a vital role in our functioning, but are also responsible for the mechanism of excitotoxicity

A

Ca

O2

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2
Q

Metabolic and NT pools of Glutamate

A

are strictly separated

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3
Q

What (general) types or receptors can be activated by EAA?

A

ionotropic

metabotropic

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4
Q

What are the two types of Ionotropic receptors that EAA bind to

A

NMDA receptors

non NMDA receptors

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5
Q

What ion is associated with the NMDA receptor?

A

Ca2+

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6
Q

What are (3) modulatory sites for the NMDA receptor

A

glycine binding site
Mg2+ binding site
PCP binding site

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7
Q

________ is a coagonist for the NMDA receptor

A

glycine
presence of glycine required for eaa to have effect
glycine cannot open channel on its own

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8
Q

_____ has to be displaced for the NMDA channel to be open

A

Mg2+
blocks the channel from the inside
cell must depolarize for MG to leave

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9
Q

Describe the characteristic epsp caused by the NMDA receptor

A

slow onset

longer duration

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10
Q

what is responsible for the slow onset of the epsp of the NMDA receptor

A

have to remove Mg from the channel

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11
Q

what is responsible for the long duration of the NMDA epsp

A

Ca2+ conductance

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12
Q

what ion does the non-NMDA receptor transmit

A

Na

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13
Q

what are two subtypes of the non NMDA receptor?

A

AMPA receptors

Kainate receptors

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14
Q

name two differences between the AMPA and kainate receptors

A

kainate can transmit some Ca

AMPA has a benzodiazapine site that inhibits its response to NT

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15
Q

What type of epsps do non NMDA receptors produce

A

typical epsp

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16
Q

explain why non NMDA receptors are often localized at the same synapse as NMDA receptors

A

eaa can bind the non-NMDA receptor, allowing Na to flow into the cell. That causes depolarization, which can knock the Mg out of the NMDA channel. Now, if eaa binds to the NMDA receptor, Ca can now flow through the channel

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17
Q

Where are metabotropic EAA receptors located

A

pre and post synaptically

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18
Q

What is the purpose of metabotropic EAA receptors located on the presynaptic membrane

A

modulate NT release.

19
Q

What is the function of EAAs and non-NMDA receptors in the CNS

A

think PRIMARY AFFERENTS (sensory) and PREMOTOR (upper neurons)

20
Q

Overall function of EAA

A

major excitatory system in the CNS

21
Q

Function of the EAA - non - NMDA receptors

A

PRIMARY AFFERENTS

premotor (upper motor neurons)

22
Q

FUnctions of the EAA - NMDA receptors

A

long term changes in synaptic strength

learning and memory

23
Q

Functions of the EAA - metabotropic receptors

A

learning and memory

motor systems

24
Q

Getting rid of EAA - neurons AND glia

A

uptake systems
Na dependent secondary active transport
HIGH AFFINITY

25
Q

Getting rid of EAA - Glia only

A

convert to glutamine and release into the ECF ( glutamine can’t bind glutamate receptors)

neurons can then take up the glutamine and convert it to glutamate and repackage it into vesicles.

26
Q

recycling process of glutamate

A

glutamate released into synaptic cleft as NT
glia pick up excess glutamate, convert it to glutamine, and release it
glutamine is taken up by neurons and converted to glutamate
glutamate is repackaged into vesicles to be used as a NT

27
Q

EAA and NO

what receptor and what is the function

A

NMDA receptors
allow an influx of Ca which binds to calcineurin.
calcineurin activates NOS, which makes NO

28
Q

How does NOS make NO

A

NOS (stimulated by calcineurin+Ca) cleaves arginine into

NO and citrulline

29
Q

Neural functions of NO

A

longterm potentiation and memory

cardiovascular and respiratory control

30
Q

How can NO be toxic

A

leads to production of free radicals

these not only kill invading bacteria, but can also kill other cells

31
Q

Excitotoxicity definition

A

proposed to explain continuing neuronal death after an ischemic event
based on possibility that overstimulation of EAA system can cause cell death even in neurons that were not ischemic/hypoxic/anoxic

32
Q

Excitotoxicity - strongly associated with (strong evidence of involvement in)

A

cerebral ischemia/stroke
hypoxia or anoxia
mechanical trauma to CNS
hypoglycemia

33
Q

Excitotoxicity - substantial evidence of involvement in

A

epilepsy

34
Q

What happens in the area most directly affected by ischemia (the anoxic core)?

A

oxygen deprivation
cells unable to meet metabolic needs (no glucose, no atp)
depolarization
within 4 minutes, ATP goes to zero. NaKatpase shuts off, Vm depolarizes, and EAA are released.

35
Q

In excitotoxicity, what are two reasons we have high levels of EAA

A

Excessive EAA release,

unable to reuptake EAA (remember reuptake is Na dependent)

36
Q

In excitotoxitity, explain what happens to the post synaptic cell

A 
excess binding of EAA to NMDA receptors leads to increased CA influx
excess calcium activates: 
- phospholipase A2
 - calcineurin (phosphatase)
 - mu calpain ( protease)
 - apoptotic pathway

excess activation of these enzymes disrupts normal cellular function

37
Q

In excitotoxicity, how does activation of phopholipase A2 disrupt normal cellular funciton

A

releases arachidonate from membrane (chews up membrane=physical damage to membrane)

arachidonate acts on RyR on ER, causing further release of Ca from intracellular stores ( “unfolded protein response” and activation of eIF2a-kinase)

impairs function of mitochondria

38
Q

In excitotoxicity, how does activation of mu-calpain (protease) disrupt normal cellular function

A

proteolysis
esp. SPECTRIN = more structural damage to the cell
EIF4G (important in protein syntehsis)
others (metabolic imparement)

39
Q

In excitotoxicity, how does activation of calcineurin disrupt normal cell function

A

calcineruin is a phosphatase
activates NOS
increases NO synthesis

40
Q

how does the disruption of mitochondrial membrane due to excess Ca activate apoptosis

A

releases cytochrome C and Caspase 9
cyt C= marker that something dangerous is going on
Caspase 9= activates caspase 3, which is the major proapoptotic signal.
Caspase 3= proteolytic enzyme, apoptotic.

41
Q

Reperfusion Injury - oxygen returns to ischemic neuron

A

neuron is no longer “normal” –> much of this O2 will end up as a free radical somewhere (peroxides)

can kill neurons already damaged from ischemic event AND other neurons

42
Q

Reperfusion injury - O2 returns to mitochondria

A

If the mitochondria can make ATP it will, but the enzymes in the neuron that are currently activated arent NORMAL

Kinases will take the ATP and convert it to ADP and PO4
PO4 available for phophoyrlation, further modifying enzyme action

phosphorylation of EIF2a-kinase leads to a decreas in protein synthesis and activates caspase 3 which increases apoptotic signalling

43
Q

How does NO add to the damage in the excitotoxicity cascade

A

in high quantity, neuronal NO can act directly on the capillary endothelial cells, causeing damage and edema

44
Q

Prevention of excitotoxicity

A

difficult at best (this process happens starting at 4 minutes)
to date most experimentally successful treatments are pre-treatments that focus on the NMDA receptors.

Neuro I (30 decks)

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