Starburst amacrine cells amplify optogenetic visual restoration through gap junctions

Yusaku Katada; Hiromitsu Kunimi; Naho Serizawa; Deokho Lee; Kenta Kobayashi; Kazuno Negishi; Hideyuki Okano; Kenji F Tanaka; Kazuo Tsubota; Toshihide Kurihara

doi:10.1016/j.omtm.2023.05.011

Starburst amacrine cells amplify optogenetic visual restoration through gap junctions

Mol Ther Methods Clin Dev. 2023 May 12:30:1-13. doi: 10.1016/j.omtm.2023.05.011. eCollection 2023 Sep 14.

Authors

Yusaku Katada^{1

2}, Hiromitsu Kunimi^{1

2}, Naho Serizawa^{1

2

3}, Deokho Lee^{1

2}, Kenta Kobayashi⁴, Kazuno Negishi², Hideyuki Okano⁵, Kenji F Tanaka⁶, Kazuo Tsubota⁷, Toshihide Kurihara^{1

2}

Affiliations

¹ Laboratory of Photobiology, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
² Department of Ophthalmology, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
³ Department of Nutritional Sciences, Toyo University, Kita-ku, Tokyo 115-8650, Japan.
⁴ Section of Viral Vector Development, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Aichi 444-8585, Japan.
⁵ Department of Physiology, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
⁶ Division of Brain Sciences, Institute for Advanced Medical Research, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
⁷ Tsubota Laboratory, Inc, Shinjuku-ku, Tokyo 160-0016, Japan.

Abstract

Ectopic induction of optogenetic actuators, such as channelrhodopsin, is a promising approach to restoring vision in the degenerating retina. However, the cell type-specific response of ectopic photoreception has not been well understood. There are limits to obtaining efficient gene expression in a specifically targeted cell population by a transgenic approach. In the present study, we established a murine model with high efficiency of gene induction to retinal ganglion cells (RGCs) and amacrine cells using an improved tetracycline transactivator-operator bipartite system (KENGE-tet system). To investigate the cell type-specific visual restorative effect, we expressed the channelrhodopsin gene into RGCs and amacrine cells using the KENGE-tet system. As a result, enhancement in the visual restorative effect was observed to RGCs and starburst amacrine cells. In conclusion, a photoresponse from amacrine cells may enhance the maintained response of RGCs and further increase or improve the visual restorative effect.

Keywords: gene therapy; optogenetics; retina; starburst amacrine cells; visual restoration.