Cellular rules underlying psychedelic control of prefrontal pyramidal neurons.

Area of Science:

• Neuroscience
• Psychopharmacology
• Computational Biology

Background:

• Classical psychedelics are believed to enhance prefrontal cortex pyramidal cell excitability via serotonin 2A receptors (5-HT2AR).
• The precise mechanisms underlying psychedelic drug action, particularly their effects on neuronal excitability, remain incompletely understood.

Approach:

• Investigated the effects of multiple psychedelic classes on pyramidal neuron intrinsic excitability.
• Differentiated between extracellular and intracellular drug delivery effects.
• Utilized machine-learning-based data assimilation models to analyze M-current channel modulation.
• Examined the interaction between M-current activation and previously described mechanisms.

Key Points:

• Psychedelics dose-dependently suppress pyramidal neuron intrinsic excitability, challenging the prevailing hypothesis.
• A novel mechanism involving the enhancement of potassium M-current channels, independent of 5-HT2AR activation, was identified.
• Extracellular psychedelic delivery resulted in a greater decrease in excitability compared to intracellular delivery.
• M-current activation, in conjunction with other mechanisms, significantly reduces intrinsic excitability and working memory timespan.

Conclusions:

• Psychedelic drugs suppress neuronal intrinsic excitability through a novel mechanism involving M-current channel enhancement.
• This ion channel modulation occurs ubiquitously throughout the brain, independent of 5-HT2AR.
• The findings suggest that psychedelics may trigger homeostatic adjustments, contributing to their broad therapeutic potential.