Grover - Acute Neuronal Injury

Question 1

Excitotoxicity

Causes?

Answer 1

Excessive accumulation of glutamate in the extracellular space

Pathological over activation of NMDA type glutamate receptors

= Intracellular Calcium overload

- - -

Causes: Depletion of ATP, Swelling, Lysis

Question 2

Key Similarities and Differences with AMPA/kainate and NMDA receptors?

Answer 2

Same: Glutamate binding site, Na/K permeability

Differences: NMDA = Glycine binding site, Calcium permeable, pore binding site for Magnesium

Question 3

What role does Glycine play in NMDA receptors?

Answer 3

Binds with high affinity, extracellular [Glycine] usually low

Results in Glycine usually bound, so depends mostly on glutamate

Question 4

Importance of Mg²⁺ in NMDA channels?

Answer 4

Mg 2+ regulates channel by blocking current flow

Often target for dissociative anesthetics (ketamine, dextromethorphan)

Question 5

What two sources regulate the NMDA receptor?

Answer 5

1. Ligand binding (Glutamate/Glycine)
2. Membrane Potential (Mg²⁺) - “voltage gated” like

Question 6

Why are NMDA receptors not opened at same time as AMPA receptors?

Answer 6

Mg2+ blocking requires greater depolarization to open

Requires a greater temporal summation

Question 7

How do neurons control cell volume?

Answer 7

1. Controling membrane ion permeability
2. Active (ATP-dependent) ion transport (movement of Na/K particles)

Question 8

What two circumstances can cause cell volumbe regulation to become impaired?

Answer 8

1. ATP Stores depleted (lose active transport)
2. Membrane ion permeability becomes high (water will move IN to balance things)

Question 9

What types of injuries can trigger a loss of ATP production?

What is the result of this?

Answer 9

Anoxia

Aglycemia

Ischemia

First primary active transport will fail, then secondary active transport will fail as ion gradients break down

Question 10

What conditions can lead to a large increase in membrane ion permeability?

What is the end result?

Answer 10

Prolonged Seizures

Mechanical Trauma

Neurons depolarize and fire action potentials at high rate

Massive release of neurotransmitters, including Glutamate

Question 11

Clinical: What two conditions promote cytoxic edema?

Answer 11

1. Loss of Active Transport
2. Large increase in membrane ion permeability

Question 12

Why can elevated glutamate release not simply be taken up by cells?

What does this high glutamate activate?

Answer 12

Sodium gradient has already been lost, so secondary active transport is not working

Glutamate has potential to activate NMDA receptors

= Calcium INFLUX

Question 13

How is intracellular Calcium normally regulated?

Answer 13

In = Voltage and Ligand Gated Channels

Out = Plasma membrane transport, mitochondria/smooth ER, Calcium binding proteins

Question 14

Why can calcium rise during pathological conditions?

What is the result?

Answer 14

Excitotoxicity shuts down normal calcium regulation functions, no way for cell to clear intracellular calcium

Calcium becomes toxic to neurons due to:

1. Abnormal activation of lipases, proteases
2. Free Radical Production

= These combine to degrade lipid membrane

Question 15

What is result of calcium laden neurons releasing signals on the system?

Answer 15

Stimulate inflammatory response

Microglia, Astrocytes = Can disrupt blood brain barrier, and further neuron injury

Question 16

What is the order of toxicity from calcium overload?

Answer 16

Minutes (acute) - Excitotoxicity

Hours - Inflammation

Days - Apoptosis

Question 17

Clinical: What chronic conditions may excitotoxicity play a role in?

Answer 17

ALS, Huntington’s Disease, Alzheimers