Hippocampal synaptic transmission and Ca2⁺ signaling are altered by the selective 5-HT2A receptor agonist, 25CN-NBOH.
Yang Wang, Sinem Cetinkaya Karaca, Mille Deckmann Rasmussen, Jesper L. Kristensen, Kristi A. Kohlmeier
Neuroscience August 30, 2026 DOI: 10.1016/j.neuroscience.2026.08.049 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mouse hippocampal CA1 pyramidal neurons |
| Intervention | 25CN-NBOH |
| Dose | 10 μM |
| Measures | sEPSC frequency and amplitude, sIPSC frequency and amplitude, miniature events, action potential properties, intracellular calcium |
| Topics | Serotonin |
| Keywords | Calcium imaging Hippocampus ca1 Patch-clamp electrophysiology Psychedelics Serotonin 5-ht2a receptor Synaptic transmission |
| Key findings | 25CN-NBOH increases spontaneous excitatory and inhibitory synaptic transmission via action potential-dependent, 5-HT2A-independent mechanisms, while elevating intracellular calcium through 5-HT2A-dependent and glutamatergic presynaptic pathways, with no change in neuronal firing. |
Abstract
Classical psychedelics exert therapeutic effects on affective disorders, with serotonin 5-HT2A receptor activation thought to play a central role. The cellular mechanisms by which 5-HT2A signaling modulates neural circuits remain incompletely understood and may differ across mood-regulating brain regions. While psychedelic actions have been extensively studied in the medial prefrontal cortex, the hippocampus which is critical for mood, and memory has received less attention, and effects of selective 5-HT2A agonists on hippocampal neurons remain poorly characterized. Here, we examined the effects of the selective 5-HT2A agonist 25CN-NBOH on synaptic transmission, intrinsic excitability, and intracellular calcium in mouse hippocampal CA1 pyramidal neurons using whole-cell patch-clamp electrophysiology and Fura-2 AM imaging. 25CN-NBOH (10 μM) increased both spontaneous excitatory and inhibitory synaptic transmission, as indicated by elevated sEPSC and sIPSC frequency and amplitude, without affecting miniature events, suggesting action potential-dependent mechanisms. These synaptic effects persisted in the presence of the 5-HT2A antagonist MDL-100907, indicating 5-HT2A -independent synaptic facilitation. Despite increased synaptic drive, neuronal firing and action potential properties were unchanged, consistent with balanced excitation and inhibition. In contrast, 25CN-NBOH induced robust intracellular calcium elevations in CA1 neurons that were significantly reduced by MDL-100907, as well as by TTX and AMPA/NMDA receptor blockade, indicating dependence on both 5-HT2A receptor activation and glutamatergic presynaptic activity. Together, these findings reveal separable mechanisms of action: 5-HT2A-independent, presynaptic facilitation, and 5-HT2A-dependent calcium signaling. These results highlight distinct modes of hippocampal modulation by a selective 5-HT2A receptor agonist and suggest mechanisms through which psychedelics may promote plasticity-related processes.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cites 19
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- 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
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
and 14 more in the library