Richard H. Kramer, PhD

Title
Professor of Neurobiology and Vision Science

Department
Molecular & Cell Biology

Research Area
Molecular & Cell Biology; Neuroscience

Address
121 Life Sciences Addition
Berkeley, CA 94720

Email
rhkramer@berkeley.edu

Telephone
(510) 643-2406

Website
https://sites.google.com/berkeley.edu/richard-kramer-lab/home

Affiliations

Professor, Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute
CH and Annie Li Chair of Molecular Biology of Diseases
Director, Vision Science Core

Research

Exploiting neural plasticity to restore vision in retinal degenerative disease

In degenerative blinding diseases such as Retinitis Pigmentosa (RP) and Age-Related Macular Degeneration (AMD), the rod and cone photoreceptor cells die, but other neurons in the retina survive. This includes the retinal ganglion cells (RGCs), the output neurons of the retina that send visual information to the brain. We are developing photochemical tools, named “photoswitches,” to impart light-sensitivity on ion channels in RGCs, bypassing the missing rods and cones and restoring the ability of the retina to respond to light and send neural signals to visual centers in the brain.

We are demonstrating the effectiveness of photoswitches with three approaches: 1) electrophysiological recordings from the isolated retina, 2) optical imaging from the retina in the intact eye, and 3) behavioral experiments showing restored light responses in living mice. Our goal is to translate photoswitch molecules into a vision-restoring drug treatment for blind humans.

We have discovered an amazing unexpected property of photoswitches — they act on RGCs in blind retina, but they have no effect on RGCs in healthy retinas. This finding suggests that the loss of photoreceptor cells triggers dramatic physiological changes in RGCs — but what these changes are, and how the RGCs sense that the photoreceptors are lost — were, at first, complete mysteries.

Very recently, we have discovered that retinoic acid, a signaling molecule important in embryonic development, is also the signal that triggers physiological changes in RGCs in the degenerating adult retina. We are elucidating how retinoic acid alters RGC activity and how it allows photoswitches to exert their effects. Most importantly, we are developing drug and genetic interventions that reverse the functional changes in RGCs, and we have found that these manipulations significantly improve light-sensitivity in vision-impaired mice. Our hope is that these drug and genetic therapies can be translated into treatments for improving sight in low-vision humans.

Genetically-targeted photo-control of specific types of ion channels and neurotransmitter receptors in the brain.

We have genetically-engineered specific ion channels and neurotransmitter receptor proteins to enable them to permanently attach to photoswitch compounds. Once a photoswitch is attached, light either extends or retracts the molecule, such that it activates or inactivates the protein. For example, the tethered photoswitch can block or unblock the pore of a voltage-gated potassium channel or block or unblock the neurotransmitter binding site of a synaptic receptor, depending on the presence or absence of light.

We are using this approach on many types of channels and receptors, including voltage-gated potassium channels, and receptors for acetylcholine, glutamate, and GABA. For some of these we have generated knock-in mice, in which the mutation for the attachment site is inserted into the genome, enabling a photoswitch to control the endogenous neural signaling protein. This new technology provides a way to control the function of channels and receptors with high spatial, temporal and biochemical precision, in specific areas of the brain, such as the hippocampus and visual cortex.

Selected Recent Publications

Telias, M, Denlinger, B, Helft, Z, Beckwith-Cohen, B, Thornton, C, and Kramer, RH (2019)
Retinoic acid mediates pathophysiological remodeling of the retina in degenerative blindness. Neuron (in press).

Beckwith-Cohen B, Holzhausen L, Wang, T-M, Rajappa R, and Kramer, RH (2019)
Localizing proton-mediated inhibitory feedback at the retinal horizontal cell-cone synapse withgenetically-encoded pH probes. Journal of Neuroscience 39:651-662.

Tochitsky, I, Kienzler, MA, Isacoff, E, and and Kramer RH (2018)
Restoring Vision to the Blind with Chemical Photoswitches. Chemistry Reviews 118:10748-10773

Tochitsky I, Trautman J, Gallerani N, Malis JG, Kramer RH (2017)
Restoring visual function to the blind retina with a potent, safe and long-lasting photoswitch. Scientific Reports.
7:45487.

Tochitsky I, Helft Z, Meseguer V, Fletcher RB, Vessey KA, Telias M, Denlinger B, Malis J, Fletcher EL, Kramer RH (2016)
How Azobenzene Photoswitches Restore Visual Responses to the Blind Retina. Neuron. 92:100-113.

Kramer, R.H. and Davenport, C. (2015)
Lateral inhibition in the retina: The case of the missingneurotransmitter. PLoS Biology 13:e1002322.

Lin, W-C, Tsai, MC, Davenport, C, Smith, C, Veit, J, Wilson, N, Adesnik, H, and Kramer, RH (2015)
A comprehensive optogenetic pharmacology toolkit for in vivo control of GABA A receptors and synaptic inhibition. Neuron. 88:879-891.

Tochitsky, I., and Kramer, R.H. (2015)
Optopharmacological tools for restoring visual function in degenerative retinal diseases. Current Opinion in Neurobiology 34C:74-78.

Tochitsky, I., Polosukhina , P, Degtyar, V.E., Gallerani, N. Friedman , A., Van Gelder , R.N., Trauner, D., Kaufer, D. and Kramer, R.H. (2014)
Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells. Neuron 81:800-813.

Wang, T-M. , Hozhausen, L., and Kramer, R.H. (2014)
Imaging of an optogenetic pH sensor reveals that protons mediate lateral inhibition in the retina. Nature Neuroscience 17:262-268.

Tochitsky, I., Polosukhina , P, Degtyar, V.E., Gallerani, N. Friedman , A., Van Gelder , R.N., Trauner, D., Kaufer, D. and Kramer, R.H. (2014)
Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells. Neuron 81:800-813.

Kramer, RH , Mourot, A, and Adesnik H (2013)
Optogenetic pharmacology for control of native neuronal signaling proteins. Nature Neuroscience 16:816-823.

Mourot A, Fehrentz T, Le Feuvre Y, Smith CM, Herold C, Dalkara D, Nagy F, Trauner D, Kramer RH (2012)
Rapid optical control of nociception with an ion-channel photoswitch. Nature Methods. 9:396-402.

Tochitsky I, Banghart MR, Mourot A, Yao JZ, Gaub B, Kramer RH, Trauner D. (2012)
Optochemical control of genetically engineered neuronal nicotinic acetylcholine receptors. Nature Chemistry 4:105-11.

Sandoz, G., Levitz, J., Kramer, RH, and Isacoff, EY (2012)
Optical control of endogenous proteins with a photoswitchable conditional subunit reveals a role for TREK1 in GABA B signaling. Neuron 74:1005-1014.

Polosukhina A., Litt, J. Tochitsky, I, Nemargut, J., Sychev, Y., De Kouchkovsky, I., Huang, T.,Borges , K., Trauner, D. Van Gelder, R.N., and Kramer, R.H. (2012)
Photochemical restoration of visual responses in blind mice. Neuron 75:271-282.

Tian M, Xu CS, Montpetit R, Kramer RH (2012)
Rab3A mediates vesicle delivery at photoreceptor ribbon synapses. Journal of Neuroscience 32:6931-6936.