Journal
NATURE METHODS
Volume 15, Issue 10, Pages 823-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41592-018-0142-8
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Funding
- Howard Hughes Medical Institute
- Gordon and Betty Moore Foundation
- Human Frontiers Science Program
- Edmund and Lili Safra center for Brain Sciences
- NIH [NS-089491]
- Stanley Center
- NIMH [5U01MH105669-04, 1U01MH115727-01]
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Optical assays of synaptic strength could facilitate studies of neuronal transmission and its dysregulation in disease. Here we introduce a genetic toolbox for all-optical interrogation of synaptic electrophysiology (synOptopatch) via mutually exclusive expression of a channelrhodopsin actuator and an archaerhodopsin-derived voltage indicator. Optically induced activity in the channelrhodopsin-expressing neurons generated excitatory and inhibitory postsynaptic potentials that we optically resolved in reporter-expressing neurons. We further developed a yellow spine-targeted Ca2+ indicator to localize optogenetically triggered synaptic inputs. We demonstrated synOptopatch recordings in cultured rodent neurons and in acute rodent brain slice. In synOptopatch measurements of primary rodent cultures, acute ketamine administration suppressed disynaptic inhibitory feedbacks, mimicking the effect of this drug on network function in both rodents and humans. We localized this action of ketamine to excitatory synapses onto interneurons. These results establish an in vitro all-optical model of disynaptic disinhibition, a synaptic defect hypothesized in schizophrenia-associated psychosis.
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