Psychedelic neuroplasticity of cortical neurons lacking 5-HT2A receptors
Tyler G. Ekins, Chloe Rybicki-Kler, Tao Deng, Isla A. W. Brooks, Izabela Jedrasiak‐cape, Ethan Donoho, Omar J. Ahmed
Molecular Psychiatry March 1, 2026 DOI: 10.1038/s41380-025-03257-w (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | classical psychedelic drugs |
| Topics | Neuroplasticity Serotonin |
| Citations | 9 |
| Key findings | Psychedelics induce long-lasting synaptic enhancement in the retrosplenial cortex via presynaptic serotonin 2A receptors on anterior thalamic inputs, despite the absence of postsynaptic 5-HT_2A receptors. |
Abstract
Classical psychedelic drugs show promise as a treatment for major depressive disorder and related psychiatric disorders. This therapeutic efficacy stems from long-lasting psychedelic-induced neuroplasticity onto prefrontal cortical neurons and is thought to require the postsynaptic expression of serotonin 2A receptors (5-HT_2AR). However, other cortical regions such as the granular retrosplenial cortex (RSG) – important for memory, spatial orientation, fear extinction, and imagining oneself in the future, but impaired in Alzheimer’s disease – lack 5-HT_2AR and are thus considered unlikely to benefit from psychedelic therapy. Here, we show that RSG pyramidal cells lacking postsynaptic 5-HT_2A receptors still undergo long-lasting psychedelic-induced synaptic enhancement. A newly engineered CRISPR-Cas-based conditional knockout mouse line reveals that this form of psychedelic-induced retrosplenial plasticity requires presynaptic 5-HT_2A receptors expressed on anterior thalamic axonal inputs to RSG. These results highlight a broader psychedelic therapeutic utility than currently appreciated, suggesting potential for augmenting RSG circuit function in Alzheimer’s disease, post-traumatic stress disorder, and other neuropsychiatric conditions, despite the lack of postsynaptic 5-HT_2A receptors.
Comparable studies
Other preclinical and animal studies on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cited by 9
- Hormonal Influences on Psilocybin Responsivity Across the Female Lifespan: Toward Personalized Psychedelic-Assisted Therapy Psychoactives November 2, 2025
- Dual Modulation of 5-HT2A Receptors and SERT by α-Ethyltryptamine and Its Optical Isomers. ACS Chemical Neuroscience December 17, 2025
- Naturally Derived Psilocybin for Therapeutic Use: A Six-Criterion Framework for Evidence, Safety, and Benefit–Risk Considerations in Policy and Clinical Development Biomolecules July 3, 2026
- Psilocybin restores behavior and 5-HT2A signaling while reducing microglial density after chronic traumatic brain injury in rats. Cell Reports Medicine June 12, 2026
- Classic Psychedelics for Chronic Pain: A Critical Review of the Literature and Practical Advice for Clinicians. Drugs June 4, 2026
and 4 more in the library
Cites 35
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study Journal of Psychopharmacology January 13, 2015
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
and 30 more in the library