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
Nature Methods October 2018 DOI: 10.1038/s41592-018-0142-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study (in vitro and acute brain slice) Peer reviewed |
|---|---|
| Population | Cultured rodent neurons and acute rodent brain slices |
| Intervention | Ketamine |
| Topics | Esketamine Ketamine |
| Key findings | The authors report that synOptopatch enables all-optical recording of excitatory and inhibitory postsynaptic potentials in rodent neurons and slices. In primary rodent cultures, acute ketamine suppressed disynaptic inhibitory feedback, an effect the authors localize to excitatory synapses onto interneurons, and they propose this as an in vitro model of disynaptic disinhibition. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 4
- Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines Nature Communications June 3, 2019
- A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics Trends in Neurosciences December 21, 2020
- Psychoplastogens to Reduce Persistent Cognitive Symptoms for Traumatic Brain Injury as a Chronic Condition Journal of Neurotrauma October 19, 2026
- The mechanistic basis for the rapid antidepressant-like effects of ketamine: From neural circuits to molecular pathways. Progress in Neuro-Psychopharmacology and Biological Psychiatry December 1, 2023
Cites 3
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Ketamine Increases Human Motor Cortex Excitability to Transcranial Magnetic Stimulation The Journal of Physiology March 1, 2003
- Complex receptor mediation of acute ketamine application on in vitro gamma oscillations in mouse prefrontal cortex: modeling gamma band oscillation abnormalities in schizophrenia. Neuroscience December 29, 2011