CNS Channelopathies

Question 1

What is episodic ataxia?

Answer 1

Irregular and uncontrolled muscle contractions

Question 2

How many types of Episodic Ataxia are there

Answer 2

6- Type I and II are the best understood

Question 3

What is type I Episodic Ataxia

Answer 3

Autosomal Dominant 
Onset of symptoms- 10-20 years old. 
Ataxia and dizziness 
Channel affect is KCNA1 which is a Kav channel
Patients have brief attacks

Question 4

What is type II Episodic Ataxia?

Answer 4

Autosomal Dominant 
onset in children and teens 
Ataxia, vertigo, nausea, headache
Symptoms can last 30 minutes to 24 hours 
CACNA1A which is a Cav channel

Question 5

What are the general symptoms of ataxi

Answer 5

Ataxia
Trunk instability (fall over a lot) 
Vertigo (II)
Vomiting
Dizziness
Nystagmus 
Nausea 
Visual blurring due to lack of control off the eye muscles- brain sees two eye fields if the eyes don't move in unison 
People can be mistaken for being drunk due to staggering movement and slurred speech

Question 6

What is the main different between type I and II ataxia?

Answer 6

Type I- Kav Channel, symptoms are brief

Type II- Cav channels, symptoms are prolonged

Question 7

What are the triggers for Type I EA?

Answer 7

Physical or emotional stress (football ataxia family)
Sudden changes in position
Vestibular system imbalances

Question 8

Where is the K channel which is affected in type I EA and what is the impact?

Answer 8

In the cerebellum and neuromuscular junction.
The cerebellum is very important for coordinating movement.
If there are issues with the cerebellar neurons- trouble controlling muscle contractions.

Question 9

In type I EA, are the mutations loss or gain of function?

Answer 9

They are loss of function. Dominant negative. Mutations can be in the TM domains, or the intracellular loops.
Mutations are dominant negative because 4 subunits have to come together to create the channel- if one of these is mutated then the whole channel is non-functional.

Question 10

What is the effect of the channel mutation in Type I EA?

Answer 10

There is a severe loss of K current across the membrane (moving out) which means that there is increased neuronal excitability due to the lack of K hyperpolarising the membrane.
High IC K means that the cell has a more positive potential on the inside and is thus more likely to reach threshold for AP firing.
Cells fire inappropriate APs.

Question 11

Treatment for Type I EA?

Answer 11

Acetazolomide-
this is a Carbonic Anhydrase inhibitor.
This will change the pH of the body fluid (involved in the pH equation). This will have an effect on the electrical excitability of the neurons.
Can also use Na channel inhibitors to impact on AP firing.

Question 12

What are the triggers of Type II EA?

Answer 12

Physical or emotional stress.

Question 13

Where is the Ca channel affected in Type II EA found?

Answer 13

In the cerebellum.
The Purkinje cells and granule cells.
Also cell bodies in central neurons

Question 14

What are the mutations in the type II EA channel?

Answer 14

The protein is one subunit with 24 TM domains, so many point mutations affect the function of the channel.
Most are truncation mutations.
Depending on the position of the mutation and thus the truncation of the protein the symptoms can be more or less severe.

Question 15

What are allelic disorders? What does this tell us?

Answer 15

Some mutations in the Ca channel affected in Type II can also cause different diseases depending on where the mutation is.
E.g. some mutations cause familial hemiplegic migranes and Type VI spinocerebellar ataxia.
Tells us that the position of the mutation on the channel confers the phenotype.

Question 16

What is the role of the Ca channels affected in Type II EA?

Answer 16

AP activates the Ca channels which leads to Ca influx and release of NT. It is important in the spread of electrical signalling

Question 17

What is the phenotype seen in Type II EA k/o mice?

Answer 17

Up to 10 day after birth they are normal.
After 10 days they have balance problems
Ataxia, falls over with twisting movements
Death after 3-4 weeks

Question 18

Is Type II EA degenerative?

Answer 18

Yes- there is damage to the neurons in the cerebellum over time due to degeneration of the neurons.

Question 19

What is the importance of normalising cells in experiments?

Answer 19

Cell size varies and so some cells will have a higher number of channels than others which will affect the current across the membrane.
Normalising cells will remove this element and so the currents will not be affected by the size of the cell and results can be accurately compared.

Question 20

Why use Ba ions instead of Ca ions?

Answer 20

Ba has the same valance and approximate size as the Ca so it fits through the channels.
When Ca enters the cell it acts to negatively feedback on the channels to stop current flowing across them.
Ba ions do not do this and so you get a much more stable current recording.

Question 21

Are the mutations in Type II EA loss or gain of function?

Answer 21

Loss- there is a reduced current through the channel.

In the mutant channels there is a shift in the voltage dependence.,

Question 22

What is the effect of the mutation in Type II EA channels in experimental context?

Answer 22

There is a shift in voltage dependence. The channels require a higher. In the mutant, there is a shift in the maximum current recorded- it happens at a slightly more positive potential.
For the same current to be achieved as in the WT- the membrane potential needs to be more positive- there needs to be a bigger membrane depolarisation.

Question 23

Where is the highest current recorded in ion channel experiments?

Answer 23

Right at the start- when the channels first begin to open, there is an increased current and a peak current due to the driving force being in favour of influx- because of concentration gradient. As ions move in. the current goes down as the concentration gradient is altered and there is less driving force to allow for influx.

Question 24

What is the effect of the mutation in Type II EA channels in physiological conditions?

Answer 24

There will be an AP and this will reach the voltage to open the WT channels.
However, the potential to open the mutant channels is not reached- they remain closed.
They will eventually respond but it takes longer- there is also a decreased current across them when they are open-
Less vesicle fusion due to less Ca influx.
Issues with NT release in the cerebellum.
Problems controlling skeletal muscle contraction.

Question 25

What is the effect of the mutant Type II EA channels on the muscles?

Answer 25

There is loss of control of skeletal muscle due to them contracting out of time due to the delay in Ca channel opening- loss off coordination.

Question 26

Treatment for type II EA?

Answer 26

Acetazolomide- Carbonic Anydrase inhibitors- reduces body fluid pH- electrical excitability affected.

Question 27

What are the symptoms of Epilepsy?

Answer 27

Seizures- severity is very varied.
Episodic and inappropriate neuronal discharges.
Can range from absent to loss of consciousness.

Question 28

What are the four main causes of Epilepsy?

Answer 28

Brain tumour
Infection
Inherited
Trauma

Question 29

What are some forms of inherited epilepsy?

Answer 29

Names depend on the ion channel affected. 
Benign familial neonatal seizures 
Absence epilepsy
Episodic Ataxia 
Very complex classification systems

Question 30

What is the role of inhibitory interneurons?

Answer 30

Release inhibitory signals onto excitatory neurons to modulate their effect

Question 31

Roles of ion channels- 
Na
Kv
Cav
AChR
GABAa 
HCN

Answer 31

Na- depolarisation
Kv- repolarisation
Cav- release of NT at synapse
AChR- post synaptic membrane excitation
GABAa -post synaptic membrane inhibition via Cl currents
HCN- hyperpolarisation-activated cyclic nucelotide gated channel- cation channel and this aids depolarisation