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Nat Methods. 2018 Oct;15(10):823-831. doi: 10.1038/s41592-018-0142-8. Epub 2018 Oct 1.

All-optical synaptic electrophysiology probes mechanism of ketamine-induced disinhibition.

Author information

1
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
2
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
3
Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
4
Department of Biology, Section of Molecular and Computational Biology, University of Southern California, Los Angeles, CA, USA.
5
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. cohen@chemistry.harvard.edu.
6
Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA. cohen@chemistry.harvard.edu.

Abstract

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.

PMID:
30275587
PMCID:
PMC6204345
DOI:
10.1038/s41592-018-0142-8
[Indexed for MEDLINE]
Free PMC Article

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