CNS Channelopathies II

Question 1

How many ion channel mutations do you need to have an epileptic condition?

Answer 1

1 mutation in 1 ion channel

Question 2

What is the function of the inhibitory neurons

Answer 2

They fire APs and release GABA which inhibits other neurons to modulate their rate of firing. Nav1.1 is on the inhibitory neurons and this can be mutated

Question 3

How is GABA released?

Answer 3

Ca influx due to opening of the Cav channels- due to AP.

Question 4

What type of channels are GABAa receptors

Answer 4

Cl- channels. They cause hyperopolarisation

Question 5

What is the role of K channels in the excitatory neurons and what affect does a mutation in one of these channels have?

Answer 5

They mediate hyperpolarisation of the neurons- if this is mutated then the chance of firing an inappropriate AP is increased.

Question 6

What are some of the channels/receptors which can be implicated in epilepsy?

Answer 6

L and T type Ca channels in excitatory neurons
HCN
AChR

Question 7

What is the function of the Nav1.1 channel?

Answer 7

In inhibitory neuron
Involved in the generation of the AP
Leads to GABA release
24 TM domains in 4 blocks of 6- the 4th TM domain of each ‘block’ is the voltage sensor

Question 8

What is the effect of mutating the Nav1.1 channel?

Answer 8

This channel is mutated in many different types of epilepsy- it depends where it is mutated to determine which type you get. Nav1.1 mutations are loss of function.
The different mutations differ in severity

Question 9

What is the phenotype of the Nav1.1 k/o mouse?

Answer 9

At first, the AP activity is sparse and then it is reduced. There is thus less release of GABA- less inhibition on the excitatory neurons, and thus there is increased excitatory output which can lead to epilepsy

Question 10

What are some types of seizures?

Answer 10

Severity depends on type of mutation-
Mild- Febrile seizures- they are common in children and are in response to high temperatures.
If there is truncation of the protein-
Complete loss of function of the channel- severe conditions such as Myoclonic seizures

Question 11

Are mutations loss or gain of function?

Answer 11

Mainly loss, but there can be some gain of function- not really sure why this causes epilepsy

Question 12

What is the function of the Nav1.1 channel in terms of the disease?

Answer 12

On inhibitory interneurons
Loss of function
Causes increased excitatory output as a result of reduced inhibition

Question 13

What is the function of the GABAa receptor

Answer 13

On the post synaptic excitatory neuron
Loss of function
Increased excitatory output due to loss of inhibition
Could be an issue with trafficking, GABA can bind but not activate, sent for degradation etc

Question 14

What is the function of the AChR?

Answer 14

On the post synaptic membrane
Gain of function
increased excitatory output due to increased ACh activity

Question 15

What is the function of Nav1.2?

Answer 15

In excitatory neurons
Gain of function
Increased excitatory output due to excessive Nav1.2 activity
Membrane will be more depolarised at any given time so it takes less to fire an AP

Question 16

What is the function of the HCN channels?

Answer 16

This is in the excitatory dendrites.
It acts to fine tune the number of APs fired in a burst
Increased excitatory output due to loss of firing control
Membrane will be more depolarised than normal- increased AP

Question 17

What is the function of the Kv7.2 channels

Answer 17

In excitatory neurons
Loss of function
Less hyperpolarisation
Increased AP firing

Question 18

What is firing control?

Answer 18

In the CNS, neurons do not fire just one AP, they fire bursts. How many and how often these bursts occur depend on the action of K and HCN channels
Their role is to fine tube the firing
If you lose this control, then you will get increased excitatory output where you shouldn’t

Question 19

Do mutations cause the disease or just increase the risk?

Answer 19

Increase the risk (most of the time). The excessive electrical activity is not always apparent in the patient - this is why we see such variety in the severity of the seizures,

Question 20

What is a pain disorder?

Answer 20

Unpleasant sensory and emotional experience associated with actual or potential tissue damage.

Question 21

Why is pain important

Answer 21

It is a protective instinct- avoidance e.g. hot things which can cause damage to the body. There are rare pain disorders which eliminate the protective response/reflexes

Question 22

What is the channel implicated in pain disorders?

Answer 22

Nav1.7. This is the only Na channel which is present on nociceptive neurons. It mediates the depolarisation phase of the AP. It is critical for the pain response.

Question 23

What are the two types of pain disorders?

Answer 23

Loss of pain (loss of function of Nav1.7)
Enhancement of pain- erythomelalgia- this is an inherited condition and it is associated with burning pain, heat and redness. This is due to gain of function of the Nav1.7 meaning that there is inappropriate AP firing