6. EAA and Excitotoxicity

Question 1

EAA stands for excitatory amino acids, what are the two main EAAs?

Answer 1

glutamate and aspartate

Question 2

EAAs are located throughout the CNS. NMDA receptors (N-methyl-D-aspartate is exogenous). EAAs can activate the receptor leading to?

Answer 2

influx of calcium

***MODULATED by glycine

Question 3

What is needed to bind to the NMDA receptor in order for the influx of Ca to occur?

Answer 3

both glycine and EAA

Question 4

What is within the NMDA receptor and blocks the channel at resting membrane potential, not allowing the passage of Calcium?

Answer 4

Mg

Question 5

becuase of the Mg in the NMDA receptor, this makes the NMDA receptor for EAAs what kind?

Answer 5

ionotropic ligand AND voltage gated

Question 6

Within the NMDA receptor, there is also a PCP binding site which what binds and does what?

Answer 6

horse tranquilizer (PCP) binds and blocks the channel and influx of Ca

Question 7

The non-NMDA receptors are ionotropic as well but primary have an influx of what?

Answer 7

Na

Question 8

The AMPA receptors when bound by EAAs or exogenous AMPA will allow the influx of what, leading to what?

Answer 8

Na, and an EPSP

Question 9

What would benzodiazepines cause if the bound to the non-NMDA AMPA receptor?

Answer 9

reduces the amount of sodium that enters

Question 10

Kainate receptors are the second type of non-NMDA receptors which allows the influx of what when EAAs bind?

Answer 10

Na and SOME Ca

Question 11

Non-NMDA receptors produce an EPSP with short onset/duration while NMDA receptors produce what?

Answer 11

long EPSP with long duration because lots of Ca influx and Mg in the way

Question 12

What is the mechanism for how NMDA receptors depolrize in order to displace the Mg blocking the channel so Ca can come inside?

Answer 12

BOTH non and NMDA receptors are on the postsynaptic membrane and are both activated by EAA. Non NMDA opens and Na comes in, causing depolarization and Ca is able to enter NMDA channel

Question 13

The functions of non-NMDA receptors are primary sensory afferents and upper motoneurons. What about NMDA receptor functions?

Answer 13

CRITICAL in short/long term memory formation

synaptic plasticity

Question 14

EAA also have metabotropic receptors which are divided into 3 groups, which are coupled with what G protein?

Answer 14

Group 1: Gq

Group 2/3: Gi

Question 15

Metabotropic receptors for EAAs exist pre and post synaptically, presynaptically for control of NT release and postsynaptically for? (3)

Answer 15

learning memory and motor systems

Question 16

To limit the actions of EAAs, glial cells nearby the synaptic cleft will do what?

Answer 16

Take up the EAAs and make them into Glutamine (LIKE GABA

Question 17

Once glutamine is made from EAA in the glial cell, what will occur?

Answer 17

Glutamine is taken back up into the presynaptic neuron and stored as EAA (?)

Question 18

EAAs will bind to NMDA on the postsynaptic neuron and allow the influx of Ca, which binds what, activating what?

Answer 18

Ca binds Calcineurin, leading to activation of NO synthase

Question 19

When Nitric Oxide synthase is activated from activation of calcineurin, what occurs within the postsynaptic neuron?

Answer 19

Arginine is made in NO and citrulline via NOS

Question 20

The production of NO from arginine, will migrate into the presynaptic neuron since it is very lipid soluble and do what?

Answer 20

increase the release of NTs

Question 21

What are two of the main functions of NO?

Answer 21

Memory in hippocampus and cerebellum

Cardiovascular and respiratory control in pons/medulla

Question 22

What is a non-neural function of NO?

Answer 22

Macrophages release NO for vasodilation

Question 23

What are three major downsides to NO?

Answer 23

very unstable w 1/2life of 5 seconds
produces free radicals
toxic to neurons in high [ ]

Question 24

EAAs
Location:
Functions:
Ionotropic Receptors:
Metabotropic Receptors:
Other:

Answer 24

Location: Widespread
Functions: Excitatory NT
Ionotropic Receptors: AMPA/Kainate/NMDA-R
Metabotropic Receptors: 3 groups 
Other: NMDA creates NO

Question 25

Excitoxitcity has two main players known as?

Answer 25

Calcium (NMDA Receptors) | Oxygen

Question 26

What occurs after ischemia in the brain and is responsible for damage to neurons whether or not they were exposed to the ischemia?

Answer 26

Over-stimulation of the EAA system

Question 27

During a stroke, in a localized part of the brain, blood flow stops to that region. After 4 minutes O2 reaches 0, mT stop producing ATP which leads to?

Answer 27

Na/K ATPase stops working cause no ATP, leading to depolarization of neuronal cell membrane

Question 28

Once the neuronal cell membrane is depolarized, what will happen, which usually happens when cells depolarize?

Answer 28

APs occur

Question 29

Once action potentials reach the presynaptic terminal NTs are released! (like normal except this is due to lack of O2 and blood) Strokes occur in the cortex so what NT is most likely released in mass amounts?

Answer 29

EAAs! which are released into other parts of the brain

Question 30

Ok but we're fine right? cause we have the glial cells which take up EAAs and make them into glutamine. WRONG: what happens in this situation?

Answer 30

The uptake of EAA are dependent on ATP, which there is none of = increase of EAA/overstimulation

Question 31

The excess EAAs binds to the non-NMDAs which removed Mg from NMDA receptors allowing what?

Answer 31

large influx of Ca into post-synaptic cell = high intracellular [Ca]

Question 32

When there are high levels of calcium within a cell, what occurs?

Answer 32

Phospholipase A2 activity increases, which acts to release arachidonic acid from membrane = physical damage to membrane

Question 33

Due to the release of arachidonic acid from the membrane that PLA chewed into, it becomes a secondary messenger and INCREASE Ca release from Er and mT. Causing WHAT? (3)

Answer 33

ER stops making protein eIF2a-kinase activation (phosphorylation) mT dysfunction

Question 34

High levels of Ca in the cell also leads to activation of u-calpain (proteolytic enzyme). Which does what?

Answer 34

Lysis of structural proteins and eIF4G = Metabolic and Structural impairment of neurons

Question 35

With the increased numbers of Ca inside the cell, calcineurin will be activated, which activates NOS, which makes NO which will make what?

Answer 35

Free radicals (BAD) and vasodilate leading to swelling and tonsillar herniation

Question 36

As a consequence of all of the steps due to high Ca, in particular release of Ca from intracellular stores, causes mT death leading to?

Answer 36

ACTIVATION of the apoptotic pathway mT releasese cytochrome C and caspase 9 activating caspase 3 which kills neurons everywhere cause excess EAAs

Question 37

After ischemia, reprerfusion of O2 to the areas would be good... but the changes that occured do not allow it. Why is O2 bad after ischemia?

Answer 37

mT are dead, so cannot utilize O2, so O2 becomes free radicals

Question 38

Some mT may be able to use O2 to make ATP, however there are 'bad' proteins activated as compared to health ones, such as?

Answer 38

PLA, calpain, calcineurin etc

Question 39

Kinases (bad cells there d/t ischemia) take the ATP and make ADP and PO4, this phosphorylations leads to?

Answer 39

PO4+ eIF2a kinase leads to FURTHER decrease in protein synthesis and further activates caspase 3 and apoptic signaling

Question 40

What is the difference between ionotropic and metabotropic receptors?

Answer 40

Ionotropic: transport ions Metabotropic: G coupled receptor