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Richard H Kramer"Inventing new ways to control neurons with light"

Abstract :

Neurons and other excitable cells have ion channels that are activated directly by voltage, chemical messengers, temperature and mechanical forces, but not by light. Using a combination of organic chemistry and molecular biology we have constructed ion channels that can be directly controlled with light. Our first generation light-regulated channels contain a genetically engineered K+ channel protein, covalently coupled to a synthetic small molecule photoswitch. The photoswitch has a ligand that blocks ion flow through the channel pore when the molecule is in the trans configuration. Short wavelength light triggers photoisomerization to the cis configuration, removing the ligand and allowing ion flow. The photoswitch can be switched rapidly and repeatedly, allowing precise and consistent control of channel activity, and consequently neuronal firing. To circumvent the need for gene expression, we have engineered a series of second generation photoswitches that bind to wild-type K+, Na+, and Ca2+ channels, conferring light-sensitivity onto endogenous channels, enabling optical manipulation of cellular excitability. We are using these light-activated channels as "remote control" devices for non-invasive control of neural activity---an alternative to neural prosthetic devices based on implanted electrode arrays. In particular, we are introducing these channels to neurons of the retina---the one part of the nervous system that is naturally accessible to light. By converting "blind" retinal neurons (e.g. retinal ganglion cells) into artificially photosensitive cells, it may be possible to restore visual sensitivity to blind animals that have lost their natural photoreceptors (rods and cones) to degenerative diseases.

Selected publications

1. R Kramer, D Fortin, D Trauner (2009) New photochemical tools for controlling neuronal activity. Curr Opin Neurobiol.
2. Skyler L Jackman, Sue-Yeon Choi, Wallace B Thoreson, Katalin Rabl, Theodore M Bartoletti, Richard H Kramer (2009) Role of the synaptic ribbon in transmitting the cone light response. Nature Neuroscience, vol. 12 (3) pp. 303-10.
3. Doris L Fortin, Matthew R Banghart, Timothy W Dunn, Katharine Borges, Daniel A Wagenaar, Quentin Gaudry, Movses H Karakossian, Thomas S Otis, William B Kristan, Dirk Trauner, Richard H Kramer (2008). Photochemical control of endogenous ion channels and cellular excitability. Nature Methods, vol. 5 (4) pp. 331-8.