Cellular rules underlying psychedelic control of prefrontal pyramidal neurons
Tyler G. Ekins, Isla A. W. Brooks, Sameer Kailasa, Chloe Rybicki-Kler, Izabela Jedrasiak‐cape, Ethan Donoho, George A. Mashour, Jason C. Rech, Omar J. Ahmed
bioRxiv (Cold Spring Harbor Laboratory) October 23, 2023 preprint DOI: 10.1101/2023.10.20.563334 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Pyramidal neurons |
| Intervention | multiple classes of psychedelics |
| Topics | Serotonin |
| Keywords | Prefrontal cortex Consumer neuroscience Pyramidal cell Self-reference effect Cognitive psychology |
| Citations | 17 |
| Key findings | Psychedelic drugs suppress intrinsic excitability of pyramidal neurons by enhancing potassium M-current channels, independent of serotonin 2A receptor activation. |
Abstract
ABSTRACT Classical psychedelic drugs are thought to increase excitability of pyramidal cells in prefrontal cortex via activation of serotonin 2 A receptors (5-HT2 A Rs). Here, we instead find that multiple classes of psychedelics dose-dependently suppress intrinsic excitability of pyramidal neurons, and that extracellular delivery of psychedelics decreases excitability significantly more than intracellular delivery. A previously unknown mechanism underlies this psychedelic drug action: enhancement of ubiquitously expressed potassium “M-current” channels that is independent of 5-HT2R activation. Using machine-learning-based data assimilation models, we show that M-current activation interacts with previously described mechanisms to dramatically reduce intrinsic excitability and shorten working memory timespan. Thus, psychedelic drugs suppress intrinsic excitability by modulating ion channels that are expressed throughout the brain, potentially triggering homeostatic adjustments that can contribute to widespread therapeutic benefits.