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

Linlin Z. Fan, Ralda Nehme, Yoav Adam, Eun Sun Jung, Hao Wu, Kevin Eggan, Don B. Arnold, Adam E. Cohen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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.

Original languageAmerican English
Pages (from-to)823-831
Number of pages9
JournalNature Methods
Issue number10
StatePublished - 1 Oct 2018
Externally publishedYes

Bibliographical note

Funding Information:
We thank V. Joshi, K. Williams, M. Lee, and S. Begum for technical assistance. We thank V. Parot for help with analysis of spine Ca2+ data, S. Turney and the Harvard Center Brain Science (CBS) for loan of optical equipment, B. Sabatini (Harvard Medical School, Boston, MA, USA) for Rbp4-Cre mice, and C. Werley and L. Williams (Q-State Biosciences, Cambridge, MA, USA) for the mI12b plasmid. This work was supported by the Howard Hughes Medical Institute and a grant from the Gordon and Betty Moore Foundation. Y.A. was supported by a long-term fellowship from the Human Frontiers Science Program and by a postdoctoral fellowship from the Edmund and Lili Safra center for Brain Sciences. D.B.A. and E.S.J. were supported by NIH grant NS-089491. K.E. and R.N. were supported by the Stanley Center and NIMH grants (grant nos. 5U01MH105669-04 and 1U01MH115727-01).

Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.


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