Nadia Syed

Background: Autism spectrum disorder (ASD) is one of the most common neurodevelopmental diseases in children with an estimated 1 in 36 children being diagnosed yearly.¹ Genetic and environmental risk factors for the disease include advanced maternal age, toxic exposure, aberrant signaling, gene mutations, and abnormalities in subcortical pathways. The neurotransmitter, serotonin plays a significant role in normal behavioral and neurological processes including the stress response, sociability, and repetitive behaviors.² Furthermore, it is linked to both neurogenesis and neural circuit formation. SERT, a serotonin transporter involved in neural development, has shown decreased activity in autistic patients within the hippocampus, thalamus, and prefrontal cortex among other areas. Currently, serotonin modulators such as SSRIs, SNRIs, TCAs, and MAOIs are used to treat comorbid mood disorders in autistic individuals, but research into using modulators to improve neurobehavioral symptoms of autism is still in progress.³

Objective: A defect in the serotonin (5-HT) signaling system has been shown to play an important role in the pathogenesis of ASD due to its crucial function in normal neurodevelopment.

Search Methods: PubMed was used for literature search using the keywords “serotonin” and “autism” as well as clinical trials online via the National Institute of Health (NIH). The year range searched was 2017-2023.

Results: Tanaka et. al. found that knockout of one or more alleles of the SLC6A4 Sert gene, a serotonin transporter in the brain, led to reduced synaptic serotonin levels, increased serotonin in the brain, and eventually development of autistic-like social deficits in mice.⁴ Additionally, reduced tryptophan (serotonin precursor) diets given to mice improved social interaction. Wichers et. al. states that modulation of serotonin in the brain via Tianeptine (SSRE) therapy normalizes atypical brain activation of autistic patients in the inferior frontal cortex, premotor cortex, and the cerebellum.⁵ Atypical activation of these brain areas is central to the neurobehavioral symptoms of autism. Abdulamir et. al. reports that higher blood serotonin and SERT levels were found in autistic children compared to controls, with higher levels in more severely autistic patients compared to mildly autistic patients.⁶ Andersson et. al. found that PET scans showing the gray matter and brainstems of autistic patients had significantly lower SERT availability when compared to neurotypical controls.⁷ Decreased reuptake of serotonin from the synaptic cleft can lead to increased levels of serotonin in the brain and therefore of autistic symptoms. Veenstra-Vanderweele et. al. are conducting a phase 2 clinical trial which states that decreasing the activity of the serotonin 5-HT2A receptor in the CNS via inverse agonism is hypothesized to improve symptoms of behavioral rigidity in autistic patients.⁸ Pimavanserin’s precise role in decreasing 5-HT2A activation in the pre-frontal cortex and other brain areas may help to restore behavioral rigidity symptoms.

Conclusion: The role of the 5-HT serotonin signaling pathway in autism pathogenesis is complex. Evaluating what stages of development serotonin modulation occurs, what part of the brain is affected, and how exactly it is modulated can help strengthen the correlation. Decreased SERT and increased serotonin in the brain may be involved in the pathophysiology of ASD development. Therapies focused on balancing serotonin levels in the brain and periphery may help improve the neurobehavioral symptoms of autism.

Works Cited:

1. Rodnyy AY, Kondaurova EM, Tsybko AS, Popova NK, Kudlay DA, Naumenko VS. The brain serotonin system in autism. Rev Neurosci. 2023;35(1):1-20. Published 2023 Jul 10. doi:10.1515/revneuro-2023-0055
2. Bortolato M, Floris G, Shih JC. From aggression to autism: new perspectives on the behavioral sequelae of monoamine oxidase deficiency. J Neural Transm (Vienna). 2018;125(11):1589-1599. doi:10.1007/s00702-018-1888-y
3. Takumi T, Tamada K, Hatanaka F, Nakai N, Bolton PF. Behavioral neuroscience of autism. Neurosci Biobehav Rev. 2020;110:60-76. doi:10.1016/j.neubiorev.2019.04.012
4. Tanaka M, Sato A, Kasai S, et al. Brain hyperserotonemia causes autism-relevant social deficits in mice. Mol Autism. 2018;9(1):60. doi:10.1186/s13229-018-0243-3.
5. Wichers RH, Findon JL, Jelsma A, et al. Modulation of atypical brain activation during executive functioning in autism: a pharmacological MRI study of tianeptine. Mol Autism. 2021;12(1):14. Published 2021 Feb 19. doi:10.1186/s13229-021-00422-0
6. Abdulamir HA, Abdul-Rasheed OF, Abdulghani EA. Serotonin and serotonin transporter levels in autistic children. Saudi Med J. 2018;39(5):487-494. doi:10.15537/smj.2018.5.21751
7. Andersson M, Tangen Ä, Farde L, et al. Serotonin transporter availability in adults with autism—a positron emission tomography study. Nature. Mol Psychiatry 26, 1647–1658. Published 2020 Aug 26. doi:10.1038/s41380-020-00868-3
8. Veenstra-Vanderweele J, et. al. Pimavanserin for rigid-compulsive symptoms in autism spectrum disorder. NIH:Clinicaltrials.gov. Published 2025 Mar 26. ID: NCT05999240.