New approaches to epilepsy treatment: optogenetics and DREADDs

Epilepsy refers to a group of disorders that are characterized by recurrent seizures. It is a relatively common neurological condition, and is considered the most common serious (implying that there is a risk of mortality) brain disorder, affecting around 2.2 million Americans.

The seizures associated with epilepsy are not homogenous; they can have a drastically different presentation depending on the patient, the part of the brain the seizure originates in, and how much of the brain the seizure affects. For example, seizures can involve clonic activity (i.e. jerking movements), tonic activity (i.e. rigid contraction of muscles), atonia (i.e. loss of muscle activity), or any combination of motor movements and/or loss of motor activity. On the other hand, they can simply be associated with a brief and subtle loss of consciousness, as in the case of an absence seizure.

One attribute that all seizures have in common, however, is excessive neural activity. Seizures are generally characterized by an increased rate of firing in a population of neurons and/or synchronous firing (i.e. neurons that are normally activated at disparate times are all firing together, leading to large spikes in neural activity) by a neuronal population. Because seizures involve an excessive level of neural activity, ictogenesis (i.e. the generation of seizures) has commonly been considered to involve either the direct excitation of neurons or the failure of a mechanism that inhibits the excitation of neurons.

Pharmacological treatments for epilepsy have been designed from this perspective, and have generally involved drugs that either decrease neural activation or increase neural inhibition. For example, drugs like carbamazepine and lamotrigine treat epilepsy by reducing activity at sodium channels in neurons, which makes neurons less likely to fire action potentials and leads to less overall neuronal activity. Other drugs, like phenobarbital and lorazepam, actively promote neural inhibition by increasing the stimulation of gamma-aminobutyric acid (GABA) receptors. GABA receptor activation typically makes neurons less likely to fire, which also reduces overall neural activity.

Pharmacological treatments for epilepsy, however, leave much to be desired. The side effects associated with them range from minor (e.g. fatigue) to serious (e.g. liver failure), and about 30% of epilepsy cases don't even respond to current pharmacological treatments. Surgical options (e.g. removing an area of brain tissue where seizures originate) can be considered in severe cases. Clearly, however, this is an irreversible treatment and also one that lacks specificity, which means that some potentially harmless (but important) brain tissue is likely to be removed along with areas from where seizures are emerging. Although surgical procedures can allow about 60-70% of patients to be seizure free within a year after the procedure, after 10 years more than half of patients begin to experience seizures again.

One of the major limitations to the current approaches to treating epilepsy is that they lack specificity. For, even if seizure activity can be traced back to excess neural excitation or deficiencies in neural inhibition, it is clear that these problems are not occurring all of the time because--except in rare cases--seizures are intermittent and represent only a small percentage of overall brain activity. Drugs that increase inhibition or reduce excitation, however, are having these effects continually (as is surgery, of course). Thus, the treatment of epilepsy is a rather crude approach that involves exerting a constant effect on the brain in the hopes of preventing a relatively rare event.

Because of this, efforts at designing new treatments for epilepsy have focused on more selective techniques. Although these approaches--which hypothetically involve targeting only neurons involved in ictogenesis--are still a long way from being used in humans, there is some promise associated with them. One method, optogenetics, targets seizure activity by incorporating light-sensitive proteins into neurons and then controlling their activity with the application of light. Another approach, designer receptors exclusively activated by designer drugs (DREADDs), focuses on ictogenesis by incorporating genetically engineered receptors  that only respond to a specific ligand into neurons and then controlling neuronal activity through the administration of that ligand.

Optogenetics for the treatment of epilepsy

Optogenetics is a field that combines insights from optics and genetics to manipulate the activity of neurons. It generally involves the use of gene therapy techniques to promote the expression of genes that encode for light sensitive proteins called opsins. In most cases, genes for opsins are carried into an organism after being incorporated into a virus' DNA (the virus in this case is known as a viral vector) or an animal is genetically engineered to express opsin genes in certain neurons from birth. Opsin expression can be targeted to specific cell types and the proteins can be used to create receptors or ion channels that are sensitive to light. When light is delivered to these neurons--either via an optical fiber inserted into the brain or with newer technologies that allow wireless external delivery of light--the opsins are activated. This allows exposure to light to act like an on-off switch for the neurons in which opsins are expressed, making them suitable for experimental or therapeutic manipulation.

One way optogenetics can be used as a treatment for epilepsy is by promoting the expression of a light-sensitive ion channel that, when activated, allows a flow of negatively charged chloride ions into the cell. This hyperpolarizes the neuron and makes it less likely to fire an action potential. Alternatively, opsin ion channels can be expressed on GABA neurons that, when activated, cause increased GABA activity and thus promote general neuronal inhibition. Both of these approaches lead to reduced activity of neuronal populations, potentially decreasing the excessive activity associated with seizures.

When linked to some method of seizure detection, optogenetics can be used to inhibit seizure activity at the first indication of its occurrence. This has already been achieved in experimental animals. For example, Krook-Magnuson et al. (2012) promoted either the expression of inhibitory channel opsins or opsins that activate GABA neurons in different groups of mice, then monitored seizure activity using electroencephalography (EEG) after the injection of a substance that promotes seizures. When seizure activity was detected on the EEG, it automatically triggered the application of light to activate the opsins. In both groups (inhibitory channel opsins and excitatory opsins on GABA neurons), light application rapidly stopped seizures.

Thus, when combined with seizure activity monitoring, optogenetics provides a way to selectively control neural excitation, cutting seizures off as soon as they begin. Optogenetics is still a relatively new field, however, and the work in this area has not yet translated into clinical approaches with humans. There are some significant hurdles to overcome before that can happen. One involves the need for a device that can non-invasively and effectively deliver light, another concerns the need for a non-stationary device that can monitor seizure activity. Advances in wireless light delivery, however, have already been made, and an implantable device to monitor seizure activity in humans was recently tested for the first time. Therefore, while this technology is not ready to be applied to epilepsy treatment in humans yet, its use is feasible in the not-so-distant future.

DREADDs for the treatment of epilepsy

Designer receptors exclusively activated by designer drugs, or DREADDs, are another approach that addresses the desire for specificity in epilepsy treatment. The use of DREADDs involves the manipulation of genes that encode for neurotransmitter receptors, then the forced expression of those mutated genes in an experimental animal. Receptors can be engineered so they no longer respond to their natural ligand, but instead only respond to a synthetic, exogenously administered drug. DREADD expression can be targeted to specific cell populations and, like the optogenetic methods discussed above, the receptors can be used to activate inhibitory neurons or inhibit excitatory neurons.

For example, Katzel et al. (2014) modified an inhibitory muscarinic acetylcholine receptor to no longer respond to acetylcholine but instead only to a synthetic ligand called clozapine-N-oxide (CNO); they then promoted the expression of this receptor in the motor cortices of rats. They administered a seizure-causing substance, then administered CNO, and found that CNO administration significantly reduced seizure activity.

Therefore, it seems that DREADDs also have potential for the targeted treatment of epilepsy. Because activation of DREADDs only requires taking a pill, it is considered less invasive than current optogenetic approaches. However, optogenetics possesses greater temporal specificity in that it can be activated immediately upon the onset of seizure activity and terminated just as quickly. Synthetic ligands for DREADDs, on the other hand, must be administered in advance of ictogenesis to ensure the drug is available to inhibit seizure activity when it begins, and will remain active in a patient's system until the drug is metabolized by the body.

Just as with optogenetics, though, there are some hurdles that must be overcome for DREADD use to translate into the clinical treatment of epilepsy. For example, individuals tend to vary considerably in how quickly they metabolize drugs. Thus, there might be some variation in the time span of protection offered by administration of a DREADD ligand, which in the case of potentially severe seizures could be dangerous. Also, although the ligands used for DREADD activation are chosen based on their selectivity for the designer receptor, a metabolite of CNO is clozapine, a commonly-used antipsychotic drug that also activates other receptors. In rodents, this did not translate into side effects, but the potential for metabolites of synthetic ligands to be biologically active must be considered when attempting to apply the technology to human populations. 

Optogenetics and DREADDs both represent intriguing approaches to treating epilepsy in the future. The intrigue stems primarily from their ability to only target certain cells, which is likely to reduce the occurrence of side effects. Regardless, even if these technologies aren't able to be used to treat humans for a long time--or ever--they still have a place in epilepsy research. For, the use of these tools also allows us more control over seizures in experimental animals, which makes a more thorough dissection of the seizure process possible. At the very least, this should provide more insight into a dangerous, yet relatively common, neurological disorder.

Krook-Magnuson, E., & Soltesz, I. (2015). Beyond the hammer and the scalpel: selective circuit control for the epilepsies Nature Neuroscience, 18 (3), 331-338 DOI: 10.1038/nn.3943