Scn2a -deficient mice exhibit serotonergic dysfunction and altered behavioral responses to psilocybin
Brody A. Deming, Jingliang Zhang, Josephine M. Brown-Leung, Manasi Suchit Halurkar, Akila D. Abeyaratna, Rineet Ranga, Keeley Farmer, Deepti Ramasamy, Jason R. Cannon, Yang Yang
bioRxiv (Cold Spring Harbor Laboratory) November 4, 2026 preprint DOI: 10.64898/2026.11.03.764054 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study (mouse model) |
|---|---|
| Population | Scn2a-deficient mice and wild-type mice |
| Intervention | Psilocybin |
| Topics | Psilocybin Serotonin |
| Key points | Psilocybin increased sociability in Scn2a-deficient mice without affecting anxiety-like behavior, whereas wild-type mice showed decreased anxiety-like behavior without increased sociability. Scn2a-deficient mice also exhibited a reduced head twitch response, altered serotonin receptor expression in the medial prefrontal cortex, and increased spontaneous firing in the dorsal raphe nucleus. |
Abstract
Autism spectrum disorder (ASD) is a prominent neurodevelopmental disorder affecting approximately 3.2% of children in the United States. Although ASD has traditionally been considered a polygenic disorder, advances in genetic testing have identified individual genes that can contribute to its development. Large-scale whole-exome sequencing has identified variants in SCN2A , which encodes the alpha subunit of the voltage-gated sodium channel Nav1.2, as a leading monogenic cause of ASD. Social deficits are a core feature of ASD, and the serotonergic system has been implicated in the regulation of social behavior. Recent studies have demonstrated that serotonergic psychedelics, such as psilocybin, can increase sociability in mouse models of ASD. However, whether underlying genetic alterations associated with ASD influence behavioral responses to psilocybin remains poorly understood. Therefore, we investigated how Scn2a deficiency affects behavioral responses to psilocybin and whether these differences are accompanied by alterations in the serotonergic system. We found that Scn2a -deficient mice exhibited differential responses to psilocybin compared to wild-type (WT) mice. Specifically, psilocybin increased sociability in Scn2a -deficient mice without affecting anxiety-like behavior, whereas WT mice exhibited decreased anxiety-like behavior without increased sociability. Further behavioral evaluation revealed a reduced head twitch response in Scn2a -deficient mice following psilocybin administration compared to WT mice. To further investigate these differences, we examined serotonin levels and receptor expression in the medial prefrontal cortex (mPFC), a brain region implicated in social behavior and psychedelic action. Although baseline serotonin levels in the mPFC did not differ between genotypes, Scn2a -deficient mice exhibited altered serotonin receptor expression. We further characterized the serotonergic system by evaluating neuronal activity in the Dorsal Raphe Nucleus, a major source of serotonergic projections to the mPFC, and found increased spontaneous firing in Scn2a -deficient mice. Together, these findings highlight serotonergic alterations associated with SCN2A deficiency and the potential for serotonergic interventions to alleviate social deficits associated with SCN2A -related ASD.
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 |