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.

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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)
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Special Emphasis Panel (ZNS1-SRB-G (77))
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Talley, Edmund M
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University of California Berkeley
Schools of Arts and Sciences
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Lin, Wan-Chen; Tsai, Ming-Chi; Rajappa, Rajit et al. (2018) Design of a Highly Bistable Photoswitchable Tethered Ligand for Rapid and Sustained Manipulation of Neurotransmission. J Am Chem Soc 140:7445-7448
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