In a groundbreaking study poised to reshape our understanding of psychedelic pharmacology and its neural substrates, a team of scientists has elucidated the precise cellular mechanisms by which psychedelic compounds exert their effects on the brain’s prefrontal cortex. Published in the prestigious journal Translational Psychiatry, the research reveals that psychedelics directly excite specific neurons in layer V of the medial prefrontal cortex (mPFC) through activation of the 5-HT2A receptor coupled to Gq proteins. This molecular insight bridges longstanding gaps in the field and paves the way for novel therapeutic strategies targeting psychiatric conditions.
For decades, scientists have understood that psychedelics—including classic compounds like LSD and psilocybin—primarily interact with serotonin receptors, notably the 5-HT2A subtype. However, exactly how these compounds influence prefrontal cortical circuits at a cellular level has remained elusive. The new findings from Schmitz, Chiu, Foglesong, and colleagues identify that psychedelics evoke direct excitation of layer V pyramidal neurons in the mPFC by harnessing intracellular signaling cascades downstream of 5-HT2A receptors, a G protein-coupled receptor subtype predominantly coupling to the Gq/11 family.
Layer V neurons of the medial prefrontal cortex represent a critical nexus integrating cortical and subcortical inputs implicated in cognition, mood regulation, and executive function. Dysregulation of these circuits features prominently in neuropsychiatric disorders such as depression, anxiety, and schizophrenia. By directly demonstrating that psychedelics produce excitation in this specific cortical population via 5-HT2A Gq activation, the study provides a mechanistic explanation for both the profound subjective and therapeutic effects observed in humans.
Using a combination of advanced in vitro electrophysiology, pharmacological manipulations, and molecular interventions, the researchers demonstrated that psychedelic compounds produce a marked increase in action potential firing specifically in mPFC layer V neurons. This increase was abolished when 5-HT2A receptors or their downstream Gq signaling pathways were pharmacologically inhibited, conclusively linking the receptor’s Gq pathway activation to neuronal excitation. Notably, this excitation was intrinsic to the neurons themselves rather than a result of altered network activity, underscoring a direct postsynaptic effect.
These discoveries hold tremendous implications for the development of antidepressant and anxiolytic treatments. Psychedelic therapies are currently undergoing clinical trials, with early reports indicating rapid and sustained symptom relief in patients with treatment-resistant depression and PTSD. Understanding that layer V mPFC neurons serve as a direct psychedelic target provides a cellular blueprint for drug development aimed at maximizing therapeutic efficacy while minimizing side effects. Such precision medicine approaches may include designing agonists or modulators that selectively engage 5-HT2A Gq signaling in specific cortical layers.
Further elucidating the intracellular pathways activated by psychedelics, the study details how Gq protein stimulation leads to activation of phospholipase C (PLC), subsequent generation of inositol trisphosphate (IP3), and release of intracellular calcium stores. This cascade ultimately modulates ion channels, including non-selective cation channels, to promote membrane depolarization and increased excitability. This refined understanding elucidates the molecular underpinnings of the heightened cortical responsiveness and network plasticity attributed to psychedelic states.
The medial prefrontal cortex’s layered structure and heterogeneous neuronal populations present a complex organizational challenge. However, the present work’s layer-specific identification of 5-HT2A-mediated excitation advances prior findings that often lacked cellular precision. Layer V pyramidal neurons project extensively to subcortical regions such as the thalamus and striatum, implicating this excitation as a critical node for widespread brain network modulation observed in psychedelic experiences. This challenges the classical notion that psychedelics’ actions were diffuse and nonspecific.
Additionally, the research addresses conflicting reports regarding the role of Gq versus other G protein pathways, such as Gi/o or Gs, in mediating 5-HT2A receptor function. The selective involvement of Gq-related signaling in the direct excitation of layer V neurons clarifies receptor signaling bias and provides a framework for dissecting receptor pharmacology in greater detail. This specificity is crucial for avoiding untoward effects linked to recruitment of alternate pathways during therapeutic drug design.
The methodology utilized in this study combined whole-cell patch-clamp recordings from acute brain slices of murine mPFC with selective application of psychedelic compounds and specific antagonists. Genetic knockdown models targeting 5-HT2A receptors and Gq alpha subunits further confirmed causality. These rigorous approaches ensured that observed neuronal responses were not artifactual but highly physiologically relevant. The translational value is enhanced by parallel gene-expression analyses confirming receptor localization in human prefrontal tissue.
From a clinical perspective, understanding that psychedelics promote excitability in layer V mPFC neurons through 5-HT2A Gq activation could also inspire future neuromodulatory interventions. Techniques such as transcranial magnetic stimulation (TMS) might be optimized to target these neuronal populations synergistically with pharmacotherapy for enhanced outcomes. Moreover, the direct excitation of layer V neurons could underlie reported improvements in cognitive flexibility and emotional regulation in psychedelic-assisted psychotherapy.
This research also provides a foundational framework for addressing challenges in psychedelic research related to tolerance, side effects, and individual variability. Elucidating the intracellular pathways responsible for the primary neuronal excitation opens avenues to selectively modulate or desensitize specific signaling components, potentially mitigating adverse effects like anxiety or perceptual distortions. Pharmacogenomic approaches could harness these molecular insights to stratify patient populations most likely to benefit from therapy.
While the study offers transformative insights, the authors note limitations such as species differences between rodent models and human neuroanatomy. Future research will be necessary to confirm whether identical molecular and cellular processes occur in the human brain in vivo. Nonetheless, the convergence of pharmacology, neurophysiology, and molecular biology showcased here sets a new benchmark for psychedelic neuroscience.
In conclusion, the work by Schmitz and colleagues marks a major advance in decoding the neural actions of psychedelics by identifying a direct excitatory effect on medial prefrontal cortex layer V neurons mediated through 5-HT2A receptor Gq activation. This discovery elucidates fundamental neurobiological mechanisms driving psychedelic states and highlights new targets for psychiatric drug development. As the psychedelic renaissance continues to accelerate, such mechanistic insights will be integral to translating ancient mind-altering compounds into precise, effective, and safe mental health treatments.
Subject of Research:
Neurophysiological mechanisms of psychedelic compounds targeting 5-HT2A receptors in layer V medial prefrontal cortex neurons.
Article Title:
Psychedelic compounds directly excite 5-HT2A layer V medial prefrontal cortex neurons through 5-HT2A Gq activation.
Article References:
Schmitz, G.P., Chiu, YT., Foglesong, M.L. et al. Psychedelic compounds directly excite 5-HT2A layer V medial prefrontal cortex neurons through 5-HT2A Gq activation. Transl Psychiatry 15, 381 (2025). https://doi.org/10.1038/s41398-025-03611-0
Image Credits: AI Generated
