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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01NS090527-01
Application #
8827023
Study Section
Special Emphasis Panel (ZNS1-SRB-G (77))
Program Officer
Talley, Edmund M
Project Start
2014-09-30
Project End
2017-07-31
Budget Start
2014-09-30
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$768,849
Indirect Cost
$277,964
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704