Could optogenetics be the next best approach for those with untreatable epilepsy?

What is epilepsy?

Epilepsy is a neurological disorder that can cause the loss of consciousness or convulsions. These are associated with abnormal electrical activity of the neurons within the brain (1). It affects many people, and can be a difficult and frustrating disease to live with. It is common for the cause of the epilepsy to be unknown, however within infants it is common that high temperatures can trigger the epileptic seizures. This is due to their undeveloped hypothalamus, the temperature control centre of the brain. In some patients, absence seizures are common. These are where the individual has a sudden loss of activity and consciousness, which is quickly returned. In comparison, many individuals have partial seizures where one side of the brain is affected. Another type of seizure is the tonic clonic seizure – these are generalised and affect the entire brain. Both tonic clonic and partial seizures cause muscles to stiffen, the person loses consciousness and falls to the floor, and following this they usually jerk rhythmically. This often causes the individual to be confused once they awaken (2).

What is refractory epilepsy?

Many individuals that suffer from the disease can be treated with pharmacological drugs, which depress the over-excited neuronal activity within the brain. These pharmacological drugs often suppress their seizures. Sometimes this may require two or three drug combinations. Unfortunately, 20-30% of patients have what is called retractable epilepsy. This means that current drugs treatments and even combinations of pharmacological interventions cannot control their epilepsy. This can be extremely debilitating to the individual. It has been found that some people, who have treatable epilepsy at a younger age, can have a relapse, as they get older. Therefore, treatments often need to be changed to suit the individual. It is therefore common that someone can be treated well, and then develops refractory epilepsy (3).

What is optogenetics? 

Optogenetics has been known to be promising within pre-clinical trials and could be an upcoming treatment for those with refractory epilepsy. Optogenetics involves the use of light to control excitable neurons within the brain. Genes are manipulated within cells causing them to express light activated channels. These light activated channels are known as opsins, these include the photoreceptors, which we have in our own visual system. They deliver information by absorbing photons from light (8). One example is Halorhodopsin, a protein, which can be genetically inserted into cells. Halorhodopsin will cause inhibition of neural activity when activated by yellow light. These light activated proteins are placed into the neurons via viral carriers. If the virus is placed into the animal in early development then it will be passed onto the offspring of that cell, therefore all cells will be responsive to the light. This technique however, can be invasive, as a viral vector needs to be inserted and a device to deliver the light (5).

Evidence that optogenetics works

This has been trialed and tested in many rat and mice studies, and has had good results. Compared to other current treatments for refractory epilepsy, such as vagal stimulation, which have shown to be ineffective, optogenetics has a much higher promise of effect from pre-clinical trials (5). Berglind et al (2014) found that the epileptiform activity in the hippocampus of mice could be treated by optogenetics, as it showed inactivation of neurons within the hippocampus both in vitro and in vivo. Thus, providing evidence for the use of optogenetics (6).

Whilst optogenetics has shown promising results, the site of seizure initiation is usually unknown; therefore the target for optogenetic treatment may not always be clear (4). Soper et al (2016) found that optogenetic activation of the deep intermediate layers of the superior colliculous (the region of the brain mainly involved in directing eye movement towards a stimulus) suppressed seizures in the forebrain and brainstem models in rats (Figure 1). You can see that patient A after optogenetic stimulation has a lower amount of tonic seizure and clonic seizure responses. Patient B has a reduction in myoclonic jerks. Pentylenetetrazole (PTZ) was given to induce the seizures in the rats. This also suggests that the deep intermediate layers of the superior coliculous are areas of the brain suitable for targeting optogenetics (4).

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Figure 1: A1) Patient treated with PTZ and no optogentic stimulation. * myoclonic jerk, dashed line – clonic seizure response, solid line tonic seizure response. A2) The same subject with the same amount to PTZ but with 100 Hz optogentic stimulation. B1) A second subject treated with PTZ and no optogentic stimulation. Showing myoclonic jerks (*). B2) The same subject treated with PTZ and 100 Hz of optogenetic stimulation. (Soper et al 2016)

Optogenetics approach into human treatments

It is clear that the evidence for optogenetics is extremely recent and is therefore still a new approach undergoing experimentation, it may be some time before they are used in humans. Inserting these genetic modifications into human cells may have different results to those shown in rats and mice studies. It is thought that this could cause long-term changes to the brain so safety and toxicity needs to be studied. (7) Hopefully within the near future this treatment could be put to use to help those with drug-resistant and persistent epilepsy.

By Abigail Byford

Edited by Molly Campbell

1 https://www.epilepsy.org.uk/info/what-is-epilepsy

2 http://www.epilepsy.com/learn/types-seizures/tonic-clonic-seizures

3 http://www.ncbi.nlm.nih.gov/pubmed/16401617/

4 Soper C, Wicker E, Kulick CV, N’Gouemo P, Forcelli PA. (2015) Optogenetic activation of superior colliculus neurons suppresses seizures originating in diverse brain networks. Neurobiol Dis. doi: 10.1016/j.nbd.2015.12.012.

5 Wykes, R. et al. 2016. Optogenetic approaches to treat epilepsy. Journal of Neuroscience Methods. 260,pp.215-220.

6 Berglind, F. et al. 2014. Optogenetic inhibition of chemically induced hypersynchronized bursting in mice. Neurobiology of Disease. 65,pp.133-141.

7 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320957/

8 http://www.acnr.co.uk/2013/03/optogenetic-treatment-of-epilepsy/

 

 

 

 

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