Excitotoxicity

Question 0

Excitatory amino acids

Answer 0

Glutamate (mostly)

Aspartate (often found with glutamate)

Question 1

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

Answer 1

Ca

O2

Question 2

Metabolic and NT pools of Glutamate

Answer 2

are strictly separated

Question 3

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

Answer 3

ionotropic

metabotropic

Question 4

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

Answer 4

NMDA receptors

non NMDA receptors

Question 5

What ion is associated with the NMDA receptor?

Answer 5

Ca2+

Question 6

What are (3) modulatory sites for the NMDA receptor

Answer 6

glycine binding site
Mg2+ binding site
PCP binding site

Question 7

________ is a coagonist for the NMDA receptor

Answer 7

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

Question 8

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

Answer 8

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

Question 9

Describe the characteristic epsp caused by the NMDA receptor

Answer 9

slow onset

longer duration

Question 10

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

Answer 10

have to remove Mg from the channel

Question 11

what is responsible for the long duration of the NMDA epsp

Answer 11

Ca2+ conductance

Question 12

what ion does the non-NMDA receptor transmit

Answer 12

Na

Question 13

what are two subtypes of the non NMDA receptor?

Answer 13

AMPA receptors

Kainate receptors

Question 14

name two differences between the AMPA and kainate receptors

Answer 14

kainate can transmit some Ca

AMPA has a benzodiazapine site that inhibits its response to NT

Question 15

What type of epsps do non NMDA receptors produce

Answer 15

typical epsp

Question 16

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

Answer 16

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

Question 17

Where are metabotropic EAA receptors located

Answer 17

pre and post synaptically

Question 18

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

Answer 18

modulate NT release.

Question 19

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

Answer 19

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

Question 20

Overall function of EAA

Answer 20

major excitatory system in the CNS

Question 21

Function of the EAA - non - NMDA receptors

Answer 21

PRIMARY AFFERENTS

premotor (upper motor neurons)

Question 22

FUnctions of the EAA - NMDA receptors

Answer 22

long term changes in synaptic strength

learning and memory

Question 23

Functions of the EAA - metabotropic receptors

Answer 23

learning and memory

motor systems

Question 24

Getting rid of EAA - neurons AND glia

Answer 24

uptake systems Na dependent secondary active transport HIGH AFFINITY

Question 25

Getting rid of EAA - Glia only

Answer 25

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.

Question 26

recycling process of glutamate

Answer 26

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

Question 27

EAA and NO | what receptor and what is the function

Answer 27

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

Question 28

How does NOS make NO

Answer 28

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

Question 29

Neural functions of NO

Answer 29

longterm potentiation and memory | cardiovascular and respiratory control

Question 30

How can NO be toxic

Answer 30

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

Question 31

Excitotoxicity definition

Answer 31

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

Question 32

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

Answer 32

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

Question 33

Excitotoxicity - substantial evidence of involvement in

Answer 33

epilepsy

Question 34

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

Answer 34

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.

Question 35

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

Answer 35

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

Question 36

In excitotoxitity, explain what happens to the post synaptic cell

Answer 36

``` 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

Question 37

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

Answer 37

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

Question 38

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

Answer 38

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

Question 39

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

Answer 39

calcineruin is a phosphatase activates NOS increases NO synthesis

Question 40

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

Answer 40

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.

Question 41

Reperfusion Injury - oxygen returns to ischemic neuron

Answer 41

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

Question 42

Reperfusion injury - O2 returns to mitochondria

Answer 42

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

Question 43

How does NO add to the damage in the excitotoxicity cascade

Answer 43

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

Question 44

Prevention of excitotoxicity

Answer 44

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.