Fixing Faulty Neural Circuits

Question 1

Remember that channels in photoreceptors called channel rhodopsin can open or close depending on rhodopsin levels. When these channels are closed the cells hyperpolarise sending a signal on.

What can we do to treat individuals who have issues with their rhodospin / halordopsin pigments not blocking these channels to cause hyperpolarisation?

Answer 1

We can insert a compound into the membrane of the photoreceptors

This compound would be a cis / trans isomer. In one form it doesn’t block the channel rhodospin / halorhodospin channels and in other form it does. It changes form in response to light CERTAIN colours that is!

These are small organic molecules the can exist as cis / tran isomers. These help the photoreceptors to work as usual.

Question 2

What are halorhodopsin channels?

Answer 2

Well the halorrhodopsin channels respond to halorhodospin which is a pigment that breaks down in yellow light

This is sensitive to yellow light!

Question 3

What is one organic molecule example we can inject into the membrane of photoreceptors which can be used to block rhodospin channels in response to light allowing for hyperpolarisation?

This relies of cis / trans isomerism

Answer 3

A small organic molecule made up of:

Maleimide = this binds to the channel rhodopsin / halorhodospin channels

Azobenzene = this changes from when stimulated by a particular light

Quaternary ammonium = this either inhibits or activates specific channels. These block channels allowing for hyperpolarisation

Question 4

So what happens when you stimulate the organic compound which is used to replace rhodosopin / halorhodopsin pigements?

Answer 4

Stimulating this compound with light (a specific colour) turns it from as trans isomer to a cis isomer

It can now block the channel rhodospins and cause hyperpolarisation

(Note increasing the light intensity causes the isomer to go back to being a trans isomer)

Question 5

Other small organic molecules can stimulate what other areas in the retina (away from photoreceptors)

Answer 5

Can stimulate ganglion cells every time there is light. This leads to a spike in electrical activity

Question 6

What is the problem of defects in GABA receptors? And how can we treat this?

Answer 6

This can cause issues like epilepsy

How to treat?
Use a compound that can be made with the GABA A ligand to target a receptor

This binds to the GABA binding site of the receptor causing a response.

Question 7

What is retinitis?

Answer 7

This causes retinal degeneration which leads to rods and cones dying

Question 8

How to treat retinitis pigmentosa?

Answer 8

1. You can either stimulate parts of the v1 cortex in order for light to be seen with electrodes
2. Another way? THIS IS THE BEST METHOD! Artificial retinas
   - stimulate ganglion cells in the retina
   - You can do this by electrodes and locally depolarise neurones

However implanting these electrodes into the eye causes degeneration of the tissue around the electrodes.

Question 9

Two areas you should stimulate to overcome blindness?

Answer 9

Stimulate the retina (this mainly treats retinitis pigmentosa)

Or stimulate the visual cortex (this is good when the optic nerve didnt develop or is destroyed)

Question 10

What is the issue with stimulating the cortex in preference to the retina?

Answer 10

The retina performs very complex computations - so at the retina there are many different cells which project to different brain areas and have different functions

Thus its hard to know which areas in the brain to stimulate

Question 11

Issue with the artificial retinas?

Answer 11

The issue is that artificial retinas stimulate ganglion cells and not photoreceptors

Note ganglion cells have many inputs from different bipolar cells and photoreceptors, so its hard to know which ganglion we should stimulate in any scenario with electrodes.

Thus ganglion cells have too high complexity!

There are also two types of ganglion cells, parvocellular - which have small dendritic tress and magnocellular which have larger dendritic trees

You also have direction selectivity in the retina - some neurones only respond to light in certain oreintations

Question 12

How to overcome the issue of artificial retinas?

Answer 12

Use light or other means (like injecting pigments) to stimulate photoreceptors or bipolar cells in order to stimulate the deeper layers of the LGN

This will stimulate bipolar cells or even photoreceptors instead of ganglion cells

Question 13

Experiments on mice to treat retinitis pigmentosa?

Answer 13

Can express halorhodopsin in the photoreceptors of mice
Stimulation of this with yellow light allows for hyperpolarisation of the photoreceptors
This also allows for centre surround organisation and the feature of on off cells to be maintained
Retinas also have a direction selectivity maintained

(Note in the experiment the ganglion cells were recorded using patch clamp)

Experiment shows we can restore vision

Question 14

Controlling seizures ?

Answer 14

On mice models

Use channel rhodospin / halorhodospin to control

Seizures is caused by hyperactivity of cells in different regions of the brain

You can put halorhodospin channels in the excitatory cells of the brain - this allows them to hyperpolarise reducing sensitivity (can be done with a virus as vector)

Question 15

What can we do with inhibitory cells and channel rhodopsin?

Answer 15

Inject these channels. Due to lack of stimulation these channels remain open and cause depolarisation making inhibitory cells work. Reducing sensitivity again

Question 16

Problems to overcome when treating siezures?

Answer 16

Where the seizure has its origin in the brain?
To find out where to treat

Whether to target excitatory or inhibitory cells

And we need to detect seizures before they happens