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Neuro test 2 > 5.2 EAA and Excitotoxicity > Flashcards

5.2 EAA and Excitotoxicity Flashcards

1
Q

What three things are vital to our normal functioning?

A

EAA NT system, Ca2+, and Oxygen !!!

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2
Q

What are the main candidate of EAA NTs?

A

glutamate (major usually)

Aspartate

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3
Q

What is glutamate derived from?

A

a-ketogluterate

metabolic and transmitter pool is strictly segregated from one another

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4
Q

What is Aspartate often co-localized with?

A

glutamate

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5
Q

Where does aspartate serve as a NT on?

A

on its own visual cortex and pyramidal cells

metabolic and transmitter pools also strictly separated (like glutamate)

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6
Q

Where are most excitatory amino acids located?

A

most important excitatory NT system is in BRAIN

widely distributed throughout CNS (huge number of synapses!!; afferent)

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7
Q

What kind of receptors do EAAs have?

A

both ionotropic and metabotropic

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8
Q

What are the ionotropic EAA receptors? what activates them? what happens when they are activated??

A

NMDA (n-methyl-d-aspartate) receptor

NMDA= exogenous agent that activates these receptors

glutamate, aspartate= endogenous activators

when activated: channel allows influx of Ca2+

also non-NMDA receptors (AMPA and Kainate)

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9
Q

What modulatory sites are significant in NMDA receptors?

A

Glycine binding-helps open channel
Mg2+ binding site- blocks Ca
PCP binding site- blocks ca

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10
Q

What is important about the glycine binding site?

A

have multiple modulatory sites

glycine= required co-agonist, but alone can’t open channel

needs EAA to bind ALSO

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11
Q

What is important about the Mg2+ binding site?

A

within channel itself

blocks channel at RMP so Calcium CANT get in !!

makes NMDA receptor both ligand- and voltage- gated

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12
Q

Whats important about the PCP binding site?

A

ALSO blocks Ca channel

horse tranquilizer (ketamine)

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13
Q

What are non-NMDA receptors? What are the types?

A

Ionotropic- primary Na influx

Two main types: AMPA and Kainate

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14
Q

How do AMPA receptors work?

A

AMPA= exogenous agent

Glutamate/ Aspartate = endogenous ligands

primarily- Na influx –> EPSP

modulatory sites exist THO: benzodiazepines

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15
Q

How do benzodiazepines modulate AMPA receptors?

A

can bind, and they DECREASE Na by adding to sedative effect; lead to inhibition of ion (Long-term stimulation)

they bind to extracellular surface of protein, reducing amt of sodium that enters

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16
Q

How do Kainate receptors work?

A

opened by exogenous agent KAINATE or endogenous agents: glutamate and aspartate

depending on subunit composition, they can allow some Ca in but still primarily a Na channel (maybe only caviate)

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17
Q

What is the difference bw non-NMDA and NMDA receptors in making EPSPs?

A

Activation of the non-NMDA receptors produces a typical EPSP with relatively short onset and duration

Activation of NMDA receptors produces a long latency EPSP with long duration

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18
Q

Why do NMDA receptors produce a longer latency and duration EPSP?

A

takes a while to get started since it takes a bit to get rid of the positive Mg+, since needs depolarization of the cell

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19
Q

What are the steps involved in co-localization of non-NMDA an NMDA receptors on the post-synaptic membrane?

A
  1. EAA released and binds to both types of receptors (and Gly binds NMDA-R)
  2. Both non-NMDA and NMDA channels open
  3. Na+ flows in via the non-NMDA channels but Ca2+ cannot enter NMDA channel bc of the Mg2+
  4. Non-NMDA receptor activation produces the typical EPSP
  5. EPSP can provide sufficient depolarization to cause Mg2+ to leave NMDA channel
  6. Ca2+ now enters NMDA channel, producing longer-lasting EPSP
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20
Q

Can non-NMDA receptors exist on post-synaptic membranes without NMDA receptors?

A

Yes, in some systems

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21
Q

What are the important functions of Non-NMDA ionotropic receptors?

A

primary sensory afferents

upper motoneurons (pre-motor neurons in physiology “speak)

too many more…

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22
Q

What are the important functions of NMDA receptors?

A

critical in short- and long- term memory formation

synaptic plasticity in many forms

23
Q

What are metabotropic EAA receptors divided into? What are they coupled to?

A

Group 1 (mGlu1/5): Gq coupled (INCREASE IP3/DAG)

Group 2(mGlu2/3) and group 3 (mGlu4/6/7/8)= Gi coupled (DECREASE cAMP)

24
Q

Metabotropic EAA receptors exist both pre- and post-synaptically. What are the functions of each?

A

Pre-synaptic: control NT release

Post-synaptic: learning, memory, motor systems

25
Q

How does removal of EAA from the synapse occur?

A

by astrocytes (glial cells) and neurons

uses: Na-dpdt secondary active transport, high affinity systems, loss of Na gradient will SLOW uptake down considerably
astrocytes: glutamate-glutamine cycle may occur- astrocytes take up glutamate, convert to glutamine, glutamine released back into extracellular space for neuront to take it back up

26
Q

How does removal of EAA from the synapse occur?

A
  1. EAA is released and it can be taken up by glial cell by a transporter
  2. glial cell will break down EAA–> glutamine(inactivate)
  3. Glutamine released into ECF, taken up by presynapatic neuron
  4. Glutamine made into glutamate in neuron (becomes second source of glutamate for neurons)
27
Q

What happens if the glutamate-glutamine cycle is disrupted?

A

it decreases amt of glutamate released by neurons, limiting actions of EAA?

28
Q

what are the functions of EAA system?

A

EAA Rs are distributed throughout brain and spinal cord and constitute major excitatory system in brain and spinal cord of humans!

30% synapses have receptors

75% of ALL excitatory neurotransmission is responsibility of EAA

29
Q

What is the general effect of EAA at metabotropic receptors?

A

decrease in synaptic excitability; usually long-term efect; ot always direct

synaptic plasticity

30
Q

How is NO involved with EAAs?

A

direct result of NMDA recepter activation

calcium influx produced by receptor activation leads to CALCINEURIN activation

31
Q

What is calcineurin and how is it involved with NO signaling in EAAs?

A

it is a phosphatase which is calcium and calmodulin dependent

  • when activated:
    1. it cleaves a phosphate group from various proteins
    2. NOS is activated when phosphate group removed
    3. NOS takes an arginine and cleaves NO from it
    4. NO is very lipid soluble and can leave cell immediately
    5. this can have multiple actions
32
Q

What are some of the actions of NO?

A

induces activation of Guanylyl cyclase–> cGMP formation in target cell

activation of Ca-dependent K+ channel

SM cell relaxation: cGMP (used to be known as EDRF); major inhibitory NT in gut, causing relaxation

CNS: changes in presynpatic neuron related to LT potentiation

major effect= not neural; one of major controls of cerebral vasculature

33
Q

What happens in high concentrations of NO?

A

free radical production–> leads to peroxidation of membrane lipids, so membrane less fluid and damaging the membrane

–> inappropriate protein nitrosylation

34
Q

What are some of the neural functions of NO?

A

long-term potentiation of memory; in hippocampus and cerebellum

CV and respiratory control of pons and medulla

35
Q

What is an interesting function of NO mentioned in class?

A

also acts as a NT and works backward from postsynaptic to presynaptic cell and causes changes on that presynaptic cell–> which will cause increased release of NT

36
Q

If you block NO in Pons, what happens?

A

can produce apneusis (abnormal breathing)

37
Q

What are some non-neural functions of NO?

A

immunological- part of INNATE immunity (Macrophages release NO in environment bc toxic in high levels)

Cardiovascular- EDRF; vascular SM relaxation

38
Q

What is the downside/negative side of NO?

A

very unstable - half life about 5 seconds

leads to pdtion of free radicals and in high concentration toxic to neurons

39
Q

What are the two major players of excitotoxicity?

A

Calcium (NMDA receptors) and Oxygen

40
Q

What is excitotoxicity?

A

proposal that over-stimulation of EAA occurs after ischemia in brain and is responsible for damage to neurons whether or not they were exposed to ischemia

41
Q

What is excitotoxicity involved in most likely?

A

strokes, global hypoxia or anoxia, traumatic injury to brain, and hypoglycemia

also strong evidence for involvement in epilepsy

42
Q

How does anoxia/ischemia increase cytoplasmic Ca2+ levels: What is Step 1?

A
  1. Depolarization fo membrane:

Stroke occurs with immediate loss of blood flow–> within 4 minutes O2 levels drop to 0 near mitochondria and ATP pdtion ceases–> Na/K Atpase activity drops QUICK–> depolarization of neurona cell membrane

43
Q

How does anoxia/ischemia increase cytoplasmic Ca2+ levels: What is Step 2?

A
  1. Action Potentials:

Resting Vm equivalent of pushing ball up hill; that AP was equivalent to ball ROLLING down hill

as neurons depolarize, they reach threshold, and voltage gated Na channels open, leading to APs (even tho no ATP)

dont actually mess up gradient!

44
Q

How does anoxia/ischemia increase cytoplasmic Ca2+ levels: What is Step 3?

A
  1. Releasing the EAA:

release of NT into trough/cleft

bc so many synapses in cortex use EAA, this results in lot of EAA released into many diff. parts of brain !!

45
Q

What is the issue after ischemic event and release EAA?

A

gradient for Na is going away, so not only releasing a lot of glutamate, you cant take it away!! it accumulates in synapses and is even measurable in CSF

Releasing TOO MUCH EAA!!!

46
Q

Anoxia/ischemia and Ca2+ levels: how is there increasing Ca levels in postsynaptic cell?

A

Step 4: increasing Ca levels in post-synaptic cell

many synapses express both non-NMDA and NMDA receptors

activation of non-NMDA produces depolarization, forcing Mg2+ out of Ca channel, allowing Ca to get into postsynaptic cell

47
Q

what are the consequences of high intracellular Ca2+?

A
  1. Increase in phospholipase A activity
  2. activation of mu-calpain (proteolytic enzyme)
  3. activation of calcineurin
  4. activation of apoptotic pathway
48
Q

What is wrong with having an increase in phospholipase A activity?

A

acts on membrane to release arachidonic acid–> physical damage to the membrane with high activation

arachidonic acid becomes another messenger and leads to Ca2+ release from ER and mitochondria, unfolded protein response (ER stops making proteins), eIF2a-kinase activation, and mitochondrial dysfunction

49
Q

What is wrong with the excess activation of mu-calpain?

A

involved with proteolysis of structural proteins, including spectrin

proteolysis of other enzymes, proteins, and eIF4G (which disrupts protein synthesis)

also leads to METABOLIC AND STRUCTURAL IMPAIRMENT OF NEURONS !!!

50
Q

What is wrong with excess activation of calcineurin?

A

get excess production of NO via NOS

  • NO has short half life so breaks down to free radicals and free radicals are toxic!! affect neurons, protected or not
  • leads to vasodilation and swelling
51
Q

What is wrong with activation of apoptotic pathway?

A

can be directly or consequence of previous steps, in particular release of calcium from intracellular stores

mitochondrial release of enzymes (caspase 9)–> activation of caspase 3–> pro-apoptosis!!!

52
Q

Why is bringing oxygen not going to work after ischemia?

A

point of no return!! actually contributes to damage

mitochondria have released many of their enzymes, this impairs their ability to use oxygen to make ATP; so the oxygen will make FREE RADICALS (since cant use enzymes to take oxygen and make ATP)

some mitochondria may still be able to synthesize ATP, but not used by right set of enzymes compared to healthy state

53
Q

How are kinases involved in reperfusion after ischemia?

A

kinases take ATP–> ADP and phosphate

phosphorylation (that normally dont see), further modifying enzyme action

PHOSPHORYLATION OF eiF2a–> leads to FURTHER decrease of protein synthesis –> FURTHER activates caspase 3–> FURTHER increases apoptotic signaling

Neuro test 2 (15 decks)

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