Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy
| Autor: | Lori L. McMahon, Allie J. Widman |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Scopolamine Population Action Potentials Pharmacology Hippocampus Receptors N-Methyl-D-Aspartate Partial agonist Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Interneurons Muscarinic acetylcholine receptor medicine Rapastinel Animals education Depressive Disorder education.field_of_study Neuronal Plasticity Multidisciplinary Chemistry Pyramidal Cells Antagonist Antidepressive Agents Rats 030104 developmental biology medicine.anatomical_structure PNAS Plus Disinhibition Synapses NMDA receptor Ketamine medicine.symptom Pyramidal cell Excitatory Amino Acid Antagonists 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences. 115 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Low-dose ketamine, an open-channel N-methyl d-aspartate receptor (NMDAR) antagonist, mediates rapid antidepressant effects in humans that are mimicked in preclinical rodent models. Disinhibition of pyramidal cells via decreased output of fast-spiking GABAergic interneurons has been proposed as a key mechanism that triggers the antidepressant response. Unfortunately, to date, disinhibition has not been directly demonstrated. Furthermore, whether disinhibition is a common mechanism shared among other antagonists with rapid antidepressant properties in humans has not been investigated. Using in vitro electrophysiology in acute slices of dorsal hippocampus from adult male Sprague–Dawley rats, we examined the immediate effects of a clinically relevant concentration of ketamine to directly test the disinhibition hypothesis. As a mechanistic comparison, we also tested the effects of the glycine site NMDAR partial agonist/antagonist GLYX-13 (rapastinel), the GluN2B subunit-selective NMDAR antagonist Ro 25-6981, and the muscarinic acetylcholine receptor (mAChR) antagonist scopolamine. Low-dose ketamine, GLYX-13, and scopolamine reduced inhibitory input onto pyramidal cells and increased synaptically driven pyramidal cell excitability measured at the single-cell and population levels. Conversely, Ro 25-6981 increased the strength of inhibitory transmission and did not change pyramidal cell excitability. These results show a decrease in the inhibition/excitation balance that supports disinhibition as a common mechanism shared among those antagonists with rapid antidepressant properties. These data suggest that pyramidal cell disinhibition downstream of NMDAR antagonism could serve as a possible biomarker for the efficacy of rapid antidepressant therapy. |
| Databáze: | OpenAIRE |
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