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

30 Scopus citations

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.

Original languageAmerican English
Pages (from-to)823-831
Number of pages9
JournalNature Methods
Volume15
Issue number10
DOIs
StatePublished - 1 Oct 2018
Externally publishedYes

Bibliographical note

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

Fingerprint

Dive into the research topics of 'All-optical synaptic electrophysiology probes mechanism of ketamine-induced disinhibition'. Together they form a unique fingerprint.

Cite this