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Optogenetic Control of Endogenous Ca2+ Channels in Vivo

Memory improvement by light-elevated concentration of calcium ions proven for the first time in the world

“This study proved that the short-term memories of mice nearly doubled when increasing the calcium ion concentration in the hippocampus, the part of the brain in charge of spatial memories. Since this is the first study directly proving a memory increase in mice by the light-induced increment of the calcium ion concentration, researchers in the field of calcium ion-related diseases and amnesia are paying close attention to this case. Based on this study, it is expected that proper treatments for a number of diseases caused by calcium ion concentration problems could be found. Furthermore, if a technology that could adjust the photoreceptors of plant using infrared rays is developed and combined with the result of this study, more useful technologies could be introduced allowing the calcium ion concentration in the cells deep within the human body to be adjusted by penetrating light.”

Opening up possibilities of brain function improvement as well as new treatments for diseases related to in-vivo calcium ions
Calcium ions are involved in almost all vital phenomena, including cell growth, neural transmission, and muscular contraction. Thus, problems in the calcium ion adjustment mechanism lead to a number of diseases such as cognitive impairment, ataxia (a symptom in which a person cannot make certain movements despite no particular problem in the muscles), or cardiac arrhythmia. Medication or electrostimulation has been used as a treatment for such illnesses, but those have severe side effects. Against this backdrop, studies in the field of optogenetics (a biological technique that induces various reactions of a cell using light by introducing a photoreceptor protein of a plant into the animal cell) is in the spotlight as an effective alternative to existing treatments.

Against this backdrop, Professor Heo, Won-Do and his team at KIB took note of optogenetics and proved the improvement in memory by adjustment of the calcium ion concentration for the first time in the world in a study entitled, ‘Optogenetic control of endogenous Ca2+ channels in vivo’. This optogenetic controlling technology combined the photoreceptor proteins of a plant and STIM1, a gatekeeper protein controlling the on/off of the calcium channel in the human body, and applied blue light to it. By doing so, the calcium ions could penetrate the cells (OptoSTIM1, ‘optogenetic remote control’). The calcium ion channel was opened when applying the blue light, while the channel was shut when the light was turned off. The amount of calcium ion induced and residual time can be adjusted by the intensity and exposure time of the light. It was also possible to reduce the calcium ion concentration by cutting off the light. This technology was tested on mice; the mice harboring OptoSTIM1 were divided into two groups, one of which was light illuminated while the other was not. After the light stimulation, an electric shock was given to both groups to see which group had the most vivid fear memories the next day. It was found that the memories in mice with stimulated OptoSTIM1 were more than twice as powerful as those of the other group.

This study took five years in total; until 2011, researchers conducted studies to decide which plant’s photoreceptor should be used in convergence with the gatekeeper protein STIM1 and which location would be the most appropriate for activation of the fusion protein in a cell. As the design of the fusion protein was completed, the focus of the study shifted to what reactions of a cell could be induced or adjusted by the in-vivo calcium ions until 2013. Since then to 2015, when this study was published, studies on OptoSTIM1 in-vivo activation by light with human embryonic stem cells, zebrafish, and mice were mostly conducted to examine the universality of this technology.

The ‘Optogenetic control of endogenous Ca2+ channels in vivo’ has been widely acclaimed as a revolutionary research performance; it was introduced in Nature Biotechnology as a cover article in 2015. This technology is expected to be used in treatments for a number of mental disorder such as dementia, Parkinson’s disease, and depression, diseases known to be caused by the abnormal calcium ion mechanism. It is also expected that this technology can be used as a platform on which potential substances for new medicines can be discovered in a fast and effective manner by identifying the substances affecting the calcium ion concentration among the vast amount of compounds.

Prof. Heo, Won Do
2015 Annual Report

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