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Flashcards in Excitotoxicity Deck (45):
0

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

Ca
O2

1

Excitatory amino acids

Glutamate (mostly)
Aspartate (often found with glutamate)

2

Metabolic and NT pools of Glutamate

are strictly separated

3

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

ionotropic
metabotropic

4

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

NMDA receptors
non NMDA receptors

5

What ion is associated with the NMDA receptor?

Ca2+

6

What are (3) modulatory sites for the NMDA receptor

glycine binding site
Mg2+ binding site
PCP binding site

7

________ is a coagonist for the NMDA receptor

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

8

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

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

9

Describe the characteristic epsp caused by the NMDA receptor

slow onset
longer duration

10

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

have to remove Mg from the channel

11

what is responsible for the long duration of the NMDA epsp

Ca2+ conductance

12

what ion does the non-NMDA receptor transmit

Na

13

what are two subtypes of the non NMDA receptor?

AMPA receptors
Kainate receptors

14

name two differences between the AMPA and kainate receptors

kainate can transmit some Ca
AMPA has a benzodiazapine site that inhibits its response to NT

15

What type of epsps do non NMDA receptors produce

typical epsp

16

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

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

17

Where are metabotropic EAA receptors located

pre and post synaptically

18

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

modulate NT release.

19

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

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

20

Overall function of EAA

major excitatory system in the CNS

21

Function of the EAA - non - NMDA receptors

PRIMARY AFFERENTS
premotor (upper motor neurons)

22

FUnctions of the EAA - NMDA receptors

long term changes in synaptic strength
learning and memory

23

Functions of the EAA - metabotropic receptors

learning and memory
motor systems

24

Getting rid of EAA - neurons AND glia

uptake systems
Na dependent secondary active transport
HIGH AFFINITY

25

Getting rid of EAA - Glia only

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

recycling process of glutamate

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

EAA and NO
(what receptor and what is the function)

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

28

How does NOS make NO

NOS (stimulated by calcineurin+Ca) cleaves arginine into
NO and citrulline

29

Neural functions of NO

longterm potentiation and memory
cardiovascular and respiratory control

30

How can NO be toxic

leads to production of free radicals
these not only kill invading bacteria, but can also kill other cells

31

Excitotoxicity definition

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

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

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

33

Excitotoxicity - substantial evidence of involvement in

epilepsy

34

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

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

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

Excessive EAA release,
unable to reuptake EAA (remember reuptake is Na dependent)

36

In excitotoxitity, explain what happens to the post synaptic cell

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

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

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

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

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

39

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

calcineruin is a phosphatase
activates NOS
increases NO synthesis

40

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

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

Reperfusion Injury - oxygen returns to ischemic neuron

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

Reperfusion injury - O2 returns to mitochondria

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

How does NO add to the damage in the excitotoxicity cascade

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

44

Prevention of excitotoxicity

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.