Shining a light on optogenetics and epilepsy
Dr Alfredo Gonzalez-Sulser
ERUK Emerging Leader Fellow
University of Edinburgh
This week’s ERUK Research Blog features Dr Alfredo Gonzalez-Sulser, based at the University of Edinburgh. Dr Gonzalez-Sulser was awarded an ERUK Emerging Leader Fellowship Award in 2016, to research the use of optogenetics in blocking seizures in temporal lobe epilepsy. But what is optogenetics and how does it work?
I was just at the start of my PhD in 2009 at Georgetown University in the US when the lab gathered in a small meeting room to discuss a paper that had recently come out in one of the premier science journals in the world, Nature1. We had a very hard time understanding the text and we had to re-read and re-read to get the full picture. The article did not only contain the usual terms about the electrical signals in brain cells that we were well-versed in, but it also talked about using light to control the activity of cells. It sounded like science-fiction to me!
Brain cells are known as neurons and are not typically exposed to light (being inside your head) so are not especially sensitive to it. Yes, too much hot light could burn them if exposed to it, but neurons usually only take in information through specialised sensory organs like the eyes and ears. So how did these clever researchers from California manage to make neurons do their will by shining light on them?
It turns out that there are very old microscopic algae found in lakes, which have evolved the ability to move away from direct sunlight in order to not to be damaged by the heat generated by light. They do this by placing little channels within their membranes that open when they sense light. The channels let ions through, essentially allowing an electrical current to move into the cell. This electrical current then makes flagella (little algae legs) kick and make the algae move. Neurons work in a similar manner in that they also have channels in their membranes that open to let electrical currents through. For example, when a neurotransmitter attaches to a neuron it opens its membrane channels, activating the brain cell. The scientists were able to make neurons express these special membrane channels from the algae. When they were shown light it activated neurons, without the need of chemicals or some sort of electrical shock, which were the standard ways to activate cells back then.
The true advantage of this is that it arrived at a time when genetic technologies had made large strides. In the lab we routinely use mice to study how the brain works and there are many mouse epilepsy models that are used to test new treatments and understand the mechanisms of how seizures come about. The brain is comprised of millions of brain cells and there is a plethora of types of neurons. There are large and small ones, some that have pyramid-like shapes and some that look like tiny grains, others are large and under the microscope seem like the trees of the rainforest with hundreds of branches. Another very interesting property is that some brain cells excite other neurons when they release their neurotransmitters whilst some inhibit their neighbours and stop their activity. This is a critical property in epilepsy as it is believed that sometimes there is too much excitation and not enough inhibition when seizures come about. In any case, we can separate out these different types of neurons by the genes that they express and thanks to this there are technologies that allow us to change the genes in only the specific cells we want in mice and other organisms.
This is exactly what the researchers did in the paper! They added the algae gene that makes the light-sensitive membrane channels to specific types of cells in the cortex of the brain of mice, calling the technique “optogenetics” since they were then able to optically control with light genetically defined neurons. They then placed an electrode, like an EEG, on the cortex of the brain of the animals to record the activity. Healthy brains display electrical signals that are associated with different types of behaviours such as sleep, movement and memory. What they then began to do was to change the activity of different cell types by turning on and off a light aimed at the cortex of the brain and astonishingly it allowed them to figure out how different cells contributed to the various electrical patterns they saw.
Optogenetics revolutionised neuroscience research and over the past decade the technique has become a standard tool in physiology labs around the world attempting to understand how the brain works.
In the epilepsy field, researchers published papers where by activating specific cells with light they were able to block seizures in animals2,3, it increased our understanding about how seizures emerge as by activating certain cells seizures were more likely4 and new epilepsy animal models were created by overstimulating cells with light5. During my ERUK fellowship the aim has been to use optogenetics to find even more effective cell types to activate, to block seizures in temporal lobe epilepsy. As we utilise our increasing knowledge of brain cell circuits, we are able to think of the best possible clinical interventions.
Optogenetics has spurred on the invention of new technologies that specifically target certain cell types in a similar manner, albeit with other stimuli instead of light. Some examples include “ultrasound genetics6” or “magneto genetics7”, where specific cell types express membrane channels sensitive to ultrasound and magnetic stimulation, which can pass through the skull, and therefore neurons can be stimulated by devices outside of the head. Similarly, “chemogenetics8” utilises drugs that only target brain cells artificially expressing the receptors for that drug.
I believe that these approaches, which are less invasive, as they would not require a light source to be implanted in a patient’s brain, are more likely to be utilised as treatments in the future.
The true difficulty is to genetically modify cells in patient’s brains. However, the initial steps to achieve this are already being taken, where genes that decrease the activity of brain cells are being inserted into seizure-generating areas in patients with very hard to treat types of epilepsy in an ongoing recent clinical trial. Furthermore, deep brain stimulation, where an electrode is implanted in the brain and electrically stimulates only a small area to block seizures has proven to be an effective treatment9.
These different strategies to specifically target brain areas and cell types offer potential advantages versus standard treatments, such as medicines and surgery to remove epileptic brain areas, in that they may be more effective and may have less adverse effects on other quality of life factors such as memory, speech and movement. Pre-clinical epilepsy researchers working on epilepsy models, such as myself, routinely use tools like optogenetics to further our understanding of how seizures come about and to use that knowledge to identify new therapeutic brain cell targets that might have a powerful influence over seizures. We then collaborate with clinicians to try and implement these findings and help epilepsy patients. Hopefully, the future will be brighter and brighter.
-Dr Alfredo Gonzalez-Sulser
- Sohal, V. S., Zhang, F., Yizhar, O. & Deisseroth, K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459, 698–702 (2009).
- Wykes, R. C. et al. Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy. Sci. Transl. Med. 4, 161ra152 (2012).
- Krook-Magnuson, E., Armstrong, C., Oijala, M. & Soltesz, I. On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Nat. Commun. 4, 1376 (2013).
- Lévesque, M. et al. Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy. Ann. Neurol. 86, 714–728 (2019).
- Khoshkhoo, S., Vogt, D. & Sohal, V. S. Dynamic, Cell-Type-Specific Roles for GABAergic Interneurons in a Mouse Model of Optogenetically Inducible Seizures. Neuron 93, 291–298 (2017).
- Kubanek, J. et al. Ultrasound modulates ion channel currents. Sci. Rep. 6, 1–14 (2016).
- Wheeler, M. A. et al. Genetically targeted magnetic control of the nervous system. Nat. Neurosci. 19, 756–761 (2016).
- Roth, B. L. DREADDs for Neuroscientists. Neuron 89, 683–694 (2016).
- Fisher, R. et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 51, 899–908 (2010).
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