Complex receptor mediation of acute ketamine application on in vitro gamma oscillations in mouse prefrontal cortex: modeling gamma band oscillation abnormalities in schizophrenia.
J M McNally, R W McCarley, J T McKenna, Y Yanagawa, R E Brown
Neuroscience December 29, 2011 DOI: 10.1016/j.neuroscience.2011.10.015 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro experimental study Peer reviewed |
|---|---|
| Population | Mouse neocortical slices (prelimbic cortex) from GAD67-GFP knock-in mice |
| Interventions | Ketamine Kainate selective NMDAR antagonists |
| Topics | Esketamine Ketamine |
| Key findings | Ketamine potentiated kainate-elicited gamma power in mouse prelimbic cortex slices, an effect mimicked by selective NMDAR antagonists, but ketamine also reduced peak oscillation frequency, unlike more specific NMDAR antagonists. The authors indicate the frequency reduction is mediated not through NMDAR but through slowing the decay kinetics of GABA(A) receptor-mediated inhibitory postsynaptic currents in identified GABAergic interneurons. |
Abstract
Schizophrenia (Sz), along with other neuropsychiatric disorders, is associated clinically with abnormalities in neocortical gamma frequency (30-80 Hz) oscillations. In Sz patients, these abnormalities include both increased and decreased gamma activity, and show a strong association with Sz symptoms. For several decades, administration of sub-anesthetic levels of ketamine has provided the most comprehensive experimental model of Sz-symptoms. While acute application of ketamine precipitates a psychotic-like state in a number of animal models, as well as humans, the underlying mechanisms behind this effect, including alteration of neuronal network properties, are incompletely understood, making an in vitro level analysis particularly important. Previous in vitro studies have had difficulty inducing gamma oscillations in neocortical slices maintained in submerged-type recording chambers necessary for visually guided whole-cell recordings from identified neurons. Consequently, here, we validated a modified method to evoke gamma oscillations using brief, focal application of the glutamate receptor agonist kainate (KA), in slices prepared from mice expressing green fluorescent protein in GABAergic interneurons (GAD67-GFP knock-in mice). Using this method, gamma oscillations dependent on activation of AMPA and GABA(A) receptors were reliably elicited in slices containing mouse prelimbic cortex, the rodent analogue of the human dorsolateral prefrontal cortex. Examining the effects of ketamine on this model, we found that bath application of ketamine significantly potentiated KA-elicited gamma power, an effect mimicked by selective NMDAR antagonists including a selective antagonist of NMDARs containing the NR2B subunit. Importantly, ketamine, unlike more specific NMDAR antagonists, also reduced the peak frequency of KA-elicited oscillatory activity. Our findings indicate that this effect is mediated not through NMDAR, but through slowing the decay kinetics of GABA(A) receptor-mediated inhibitory postsynaptic currents in identified GABAergic interneurons. These in vitro findings may help explain the complexities of gamma findings in clinical studies of Sz and prove useful in developing new therapeutic strategies.
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 9
- Ketamine Effects on Memory Reconsolidation Favor a Learning Model of Delusions PLoS One June 12, 2013
- Effects of Ketamine on Frontoparietal Interactions in a Rule-Based Antisaccade Task in Macaque Monkeys. Journal of Neuroscience December 11, 2024
- Effects of ketamine on frontoparietal interactions during working memory in macaque monkeys bioRxiv Preprint Server May 16, 2023
- CBD Effects on Motor Profile and Neurobiological Indices Related to Glutamatergic Function Induced by Repeated Ketamine Pre-Administration Frontiers in Pharmacology October 27, 2021
- Prelimbic NMDA receptors stimulation mimics the attenuating effects of clozapine on the auditory electrophysiological rebound induced by ketamine withdrawal. Neurotoxicology December 2018
and 4 more in the library
Cites 6
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Glutamate and the Neural Basis of the Subjective Effects of Ketamine Archives of General Psychiatry February 1, 2008
- Ketamine Disrupts Frontal and Hippocampal Contribution to Encoding and Retrieval of Episodic Memory: An fMRI Study Cerebral Cortex November 10, 2004
- Mechanisms underlying ketamine-induced synaptic depression in rat hippocampus-medial prefrontal cortex pathway. Neuroscience March 17, 2011
- Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neuroscience & Biobehavioral Reviews July 1, 2008
and 1 more in the library