December 24th, 2014
Optogenetics is emerging as one of the most exciting new tools in biomedical research. This method is based on introducing genes that encode for light-sensitive proteins into cells. A laser beam can then be used to activate the light-sensitive proteins. Many of the currently used optogenetic proteins respond to the laser activation by changing the membrane voltage potential inside the cells. This is the reason why neurons and other cells that can be excited by electrical impulses, are ideally suited for studying optogenetic responses.
The recent paper “On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy” by Esther Krook-Magnuson and colleagues in Nature Communications (published online on January 22, 2013) applies the optogenetic approach to treat seizures in mice. The researchers used mice that had been genetically modified to express the inhibitory light sensitive protein halorhodopsin (normally only found in single cell organisms but not in mammals) in neurons. They placed an optical fiber to deliver the laser light to an area of the brain where they chemically induced a specific type of seizures (temporal lobe epilepsy or TLE) in the mice.
The results were quite remarkable. Activation of the laser light reduced the seizure duration by half within just five seconds. Krook-Magnuson and colleagues then also chose a second optogenetic approach to treat the seizures. Instead of using mice that contained the inhibitory light-sensitive protein halorhodopsin, they opted for mice with the excitatory (activating) light-sensitive protein channelrhodopsin (Chr2). This may seem a bit counter-intuitive, since the problem in epilepsy is that there is too much activation of neurons. One would not necessarily want to introduce activating light-sensitive proteins into neurons that are already too active. The key to understanding their strategy is the choice of the target: a subset of GABAergic cells, which can inhibit the seizure activity in neighboring neurons. This second approach was just as effective as the first approach, which used the halorhodopsin protein.
This means that one can substantially cut down seizure duration by more than half, either by directly inhibiting seizing neurons, or by activating inhibitory neurons. This research shows that there is tremendous potential for developing novel optogenetic treatments for epilepsy. Specifically targeting selected neurons that are involved in seizure activity would be preferable to generalized treatment with medications that affect global neuronal activity and could cause side effects (as is often the case with current epilepsy medications).
It is not yet clear whether this treatment can be easily applied to humans. The linchpin of the experiment was genetically introducing the light-sensitive proteins into selected neurons of the mice. This type of targeted neuronal gene therapy would be far more difficult in humans. The other obstacle is that the light activation in the mice required implantation of an optical fiber which directed the light into a specific area of the brain. Performing such an invasive procedure in patients could carry potential risks that would need to be carefully balanced with the risks and benefits of just continuing to use anti-seizure medications. Hopefully, future improvements in gene therapy methods and light stimulation will be able to help overcome these obstacles and pave the way for a whole new class of optogenetics-based therapies in patients with epilepsy and other neurological disorders.
Krook-Magnuson, E., Armstrong, C., Oijala, M., & Soltesz, I. (2013). On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy Nature Communications, 4 DOI: 10.1038/ncomms2376
Pastrana, E. (2010). Optogenetics: controlling cell function with light Nature Methods, 8 (1), 24-25 DOI: 10.1038/nmeth.f.323