Wednesday, 3-23-NT Excitotoxicity (Karius)

Question 1

___ is an EAA dervied from OAA, documented as a NT in the visual cortex and pyramidal cells

Answer 1

Aspartate—> often found with glutamate

Question 2

What type of receptor(s) can be activated by EAA’s?

Answer 2

Both ionotropic and metabotropic

Question 3

___ is an ionotropic receptor for EAA’s that are activated by exogenous N-methyl-D-aspartate as well as by glutamate and aspartate. When it is activated, it allows Ca influx and has multiple modulatory sites, including a Glycine binding site, PCP binding site, and a Mg binding site

Answer 3

NMDA receptor

Question 4

Describe the role of Glycine when it binds to the NMDA receptor?

Answer 4

Glycine serves as a CO-AGONIST

• Presence of glycine is required for the EAA to have effect
• Glycine on its own CANNOT open the channel

Question 5

Where is the Mg binding site on the NMDA receptor?

Answer 5

Inside the channel.

-Mg blocks the channel –> channel must open and cell must be depolarized for Mg to leave

Question 6

Where is the PCP binding site on the NMDA receptor?

Answer 6

Inside the channel (internal to Mg2+ site)

-Blocks the channel

Question 7

Activation of the NMDA receptor leads to ___

Answer 7

EPSP in the post-synaptic cell–> Slow onset (Time to remove Mg), prolonged duration (Ca slower)

Question 8

What are the 2 subtypes (pharmacological) of the Non-NMDA receptors?

Answer 8

AMPA

Kainate

Question 9

In order to get rid of EAA’s, ___ utilize uptake systems that are of high affinity and are Na+ dependent secondary active transport:

Answer 9

Neurons and glia

Question 10

In order to get rid of EAA’s, ___ convert the EAA’s to glutamine and release it into the ECF

Answer 10

Glia

-Neurons take glutamine up and convert it back to glutamate

Question 11

What are some neural functions of NO?

Answer 11

• Long-term potentiation and memory

- Cardiovascular and respiratory

Question 12

__ is an EAA derived from alpha-KG; its metabolic and NT pools are strictly separated

Answer 12

Glutamate

Question 13

Describe what happens in an area most directly affected by ischemia (anoxic core):

Answer 13

With O2 deprivation, cells are unable to meet metabolic needs —> DEPOLARIZATION of membrane

-Within 4 minutes: ATP levels within neurons to 0–> Na/K ATPase ceases and Vm depolarizes

Question 14

Describe levels of EAA during CNS ischemia/excitotoxicity:

Answer 14

• High levels of EAA –> Excessive release of EAA into post-synaptic density; EAA re-uptake is Na+ dependent
• NMDA receptor activation –> Ca2+ influx

Question 15

When CNS ischemia has occurred, increased [Ca2+] initiates these 4 activating events:

Answer 15

• Activation of PLA2
• Activation of calcineurin (phosphatase)
• Activation of mu-calpain (protease)
• Activation of apoptotic pathway

Question 16

During CNS ischemia, PLA2 is activated –> release of ___ from the membrane –> causes physical damage to membrane –> arachidonate acts at ___ receptor on ER –> Release of __ from intracellular stores –> In the ER, “unfolded protein response” stops making protein, activation of ___ kinase, mitochondria function impaired

Answer 16

• arachidonate
• ryanodine
• Ca2+
• eIF2-alpha

Question 17

During CNS ischemia, activation of mu-calpain (protease) results in ___

Answer 17

-Proteolysis–> spectrin (more structural damage to cell), eIF4G (eukaryotic induction factor 4G-protein synthesis), others (metabolic impairment)

Question 18

During CNS ischemia, activation of calcineurin (a phosphatase) leads to ___

Answer 18

-Activation of Nitric Oxide Synthase –> INCREASE NO SYNTHESIS

Question 19

During CNS ischemia, the disruption of mt and ER function increases free ____

Answer 19

Cytosolic calcium

Question 20

As mt membranes are disrupted, apoptotic pathways are activated. Activation of cytochrome C and caspase 9 leads to ____

Answer 20

Activation of Caspase 3 –> proteolytic enzyme, apoptotic

Question 21

During reperfusion injury, Kinases take ATP –> ADP + PO4. This phosphorylation further modifies enzyme action. The phosphorylation of ___ leads to a decreases in protein synthesis and activates caspase __, which increases apoptotic signaling

Answer 21

• eIF2alpha kinase

- 3

Question 22

During reperfusion injury, in high quantities ___ contributes to edema by damaging capillary endothelial cells

Answer 22

NO

Question 23

Activation of NMDA receptors (ionotropic) opens a channel that allows primarily ___ to enter the cell

Answer 23

Ca–> a channel wide enough to allow Ca to enter will also allow Na to enter

Question 24

Increased __ ion inhibits the opening of the channel on an NMDA receptor

Answer 24

Hydrogen–> on the EC side of the complex

Question 25

The PCP binding site on an NMDA receptor is located where and what does it block?

Answer 25

Inside of the channel and blocks the Ca2+ current

Question 26

How is Mg2+ kicked out of the inside of the NMDA receptor?

Answer 26

• Mg2+ is bound to the site at resting membrane potential

- The Mg2+ will leave this site and allow Ca2+ current with depolarization of the cell

Question 27

AMPA receptors (Non-NMDA) are activated by exogenous AMPA, as well as glutamate or aspartate. It allows primarily ___ influx

Answer 27

Na+

Question 28

The Kainate receptor (non-NMDA) is opened by exogenous kainate (but not AMPA) as well as glutamate and aspartate. Depending on sub-unit composition, this channel may allow some ___ in the cell, but is still primarily a ___ channel

Answer 28

• Ca2+

- Na+

Question 29

___ is a rare condition in which severe, intractable seizures develop in a child. Accompanying these seizures is brain damage that ends up destroying 1 hemisphere of the brain. The only known treatment is surgical removal of the affected hemisphere.

Answer 29

Ramussen’s encephalopathy –> Abs directed against the metabotropic receptor have been found in some humans suffering from the condition

Question 30

Describe the glutamate-glutamine cycle in astrocytes:

Answer 30

Astrocytes take up the glutamate and convert to glutamine via glutamine synthetase (requires ATP) –> Glutamine is released back into the EC space for neurons to take back up –> In neurons, it is converted back to glutamate

-Disruption of this system decreases the amount of glutamate released by neurons

Question 31

___ constitute the major excitatory system in the brain and SC of humans

Answer 31

EAA

Question 32

EAA at non-NMDA receptors are all/most ___ in the spinal cord (generally excitatory synaptic transmission)

Answer 32

Primary afferents

Question 33

EAA at NMDA receptors are found throughout the CNS, but most attention paid in the ___ and related areas.

Answer 33

Hippocampus

Question 34

EAA at NMDA receptors are believed to be involved in (functionally):

Answer 34

• producing long-term changes in synaptic strength via a process known as long-term potentiation
• memory
• learning

Question 35

EAA at metabotropic recptors are widely distributed throughout the CNS. Many are presynaptic and serve to modify EAA release. The general effect is a __ in synaptic excitability (often a long-term effect).

Answer 35

Decrease

Question 36

EAA at metabotropic receptors are believed to be involved in the synaptic plasticity associated with ___

Answer 36

Learning and memory (along with NMDA receptors)

Question 37

Describe the effects of NO relative to the production of cGMP:

Answer 37

• In smooth muscle, causes relaxation
• When made by endothelial cells, it acts on smooth muscle cells to cause relaxation (cGMP)

-In the CNS, linked to changes in pre-synaptic neuron related to long-term potentiation or depression –> respiratory control, CV control, memory/learning

Question 38

What is the major NON-neural effect of NO?

Answer 38

NO is one of the major controls of cerebral vasculature: blood flow almost completely controlled by local activity

-NO is the mechanism for dilation

Question 39

In high enough concentrations, describe the effects of NO:

Answer 39

• Free radical production–> peroxidation of membrane lipids, rendering the membrane less fluid and damaging the membrane
• Inappropriate protein nitrosylation –> changes the functioning of the protein, often inhibiting it

Question 40

Excitotoxicity can be caused by:

Answer 40

• Cerebral ischemia/stroke
• Hypoxia or anoxia (strong evidence)
• Mechanical trauma to the CNS (strong evidence)
• Hypoglycemia