Cellular rules underlying psychedelic control of prefrontal pyramidal neurons

Introduction

Ekins and colleagues frame the study against the prevailing model that classical serotonergic psychedelics acutely increase excitability of prefrontal cortex (PFC) pyramidal neurons via activation of serotonin 2A receptors (5-HT2ARs), a process thought to contribute to lasting synaptic remodelling. They note that neuronal excitability has two main components — intrinsic membrane properties and synaptic input — and that prior work attributing increased intrinsic excitability to resting membrane potential (RMP) depolarisation and reduced afterhyperpolarisation does not capture all reported cellular effects of these drugs, including increased inactivation of transient sodium channels. The authors therefore identify a gap: it remains unclear whether serotonergic psychedelics universally enhance intrinsic excitability of PFC pyramidal cells (PCs) through extracellular 5-HT2AR activation. This study tests that hypothesis using an integrative approach combining whole‑cell electrophysiology, morphology, pharmacology, machine‑learning data assimilation, and computational modelling. The investigators aim to determine how different serotonergic psychedelics affect intrinsic and synaptic excitability of layer 5 PFC PCs, whether intracellular versus extracellular drug delivery matters, which ion channel mechanisms underlie any changes, and how those mechanisms might influence cell‑level correlates of working memory.