Optogenetics has revolutionized neuroscience by making it possible to use heterologously expressed light-gated ion channels and pumps to stimulate or inhibit action potential firing of genetically selected neurons in order to define ther roles in brain circuits and behavior. Since the flow of information through neural circuits depends on synaptic transmission between cells, an important next technological step is to bring optogenetic control to the neurotransmitter receptors of the synapse. The Optogenetic Pharmacology that we propose makes this possible. In this approach genetically-engineered neurotransmitter receptor channels and G protein coupled receptors (GCPRs) from synapse are derivatized with synthetic Photoswitched Tethered Ligands (PTLs) and thereby made controllable by light. Our goal is to develop this new technology to gain optical control over synaptic transmission and plasticity in the living brain for studies of neural circuits and behavio. We focus on the two fundamental synapses of the brain: the excitatory glutamatergic synapse and inhibitory GABAergic synapse. An initial series of light-regulated glutamate and GABA receptors has already been made. This series will be optimized for in vivo use and expanded to obtain comprehensive control of these synapses. The receptors are minimally-modified, with a single point mutation enabling PTL attachment. Thus they retain their normal ability to respond to neurotransmitters. However, they can be blocked to prevent normal synaptic transmission or the induction of certain forms of plasticity, or they can be activated to mimic transmission or trigger plasticity changes, with cell and subtype specificity as well as high spatial and temporal precision. The receptors integrate into synapses, and control can be exerted across broad spatial scales, from individual pre- or postsynaptic terminals, to one or more dendritic branches, to individual or groups of cells, to entire brain regions. New methods for genetic manipulation allow the modified receptors to be genomically substituted for their wild-type counterparts, exactly replicating the number and distribution of endogenous receptors in the brain. Optogenetic Pharmacology provides a powerful approach for understanding brain circuits and behavior in health and disease.

Public Health Relevance

Synaptic transmission mediates the flow of information through neural circuits. In this proposal we develop Optogenetic Pharmacology and apply it to control with light the native neurotransmitter receptors of the fundamental excitatory and inhibitory synapses of the brain. Optogenetic Pharmacology provides a powerful approach for understanding brain circuits and behavior in health and disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1-SRB-G (77))
Program Officer
Talley, Edmund M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Berkeley
Schools of Arts and Sciences
United States
Zip Code
Tochitsky, Ivan; Helft, Zachary; Meseguer, Victor et al. (2016) How Azobenzene Photoswitches Restore Visual Responses to the Blind Retina. Neuron 92:100-113
Berlin, Shai; Szobota, Stephanie; Reiner, Andreas et al. (2016) A family of photoswitchable NMDA receptors. Elife 5:
Grimm, Sasha S; Isacoff, Ehud Y (2016) Allosteric substrate switching in a voltage-sensing lipid phosphatase. Nat Chem Biol 12:261-7
Tochitsky, Ivan; Kramer, Richard H (2015) Optopharmacological tools for restoring visual function in degenerative retinal diseases. Curr Opin Neurobiol 34:74-8
Berlin, Shai; Carroll, Elizabeth C; Newman, Zachary L et al. (2015) Photoactivatable genetically encoded calcium indicators for targeted neuronal imaging. Nat Methods 12:852-8
Gaub, Benjamin M; Berry, Michael H; Holt, Amy E et al. (2015) Optogenetic Vision Restoration Using Rhodopsin for Enhanced Sensitivity. Mol Ther 23:1562-71
Reiner, Andreas; Levitz, Joshua; Isacoff, Ehud Y (2015) Controlling ionotropic and metabotropic glutamate receptors with light: principles and potential. Curr Opin Pharmacol 20:135-43
Lin, Wan-Chen; Tsai, Ming-Chi; Davenport, Christopher M et al. (2015) A Comprehensive Optogenetic Pharmacology Toolkit for In Vivo Control of GABA(A) Receptors and Synaptic Inhibition. Neuron 88:879-91
Friedmann, Drew; Hoagland, Adam; Berlin, Shai et al. (2015) A spinal opsin controls early neural activity and drives a behavioral light response. Curr Biol 25:69-74
Vafabakhsh, Reza; Levitz, Joshua; Isacoff, Ehud Y (2015) Conformational dynamics of a class C G-protein-coupled receptor. Nature 524:497-501

Showing the most recent 10 out of 15 publications