Breanna Taylor

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a range of impaired social skills, repetitive behaviors, and intellectual disability.¹ Dysregulation of serotonin is thought to play a role in the behavioral phenotypes seen in ASD as deficits in the serotonergic pathway have been linked as underlying causes of ASD.^1,2,3 There is no cure for ASD and major treatment plans include behavioral and speech therapy.⁴ However, more recent treatment options also include the use of medications and dietary restrictions that modulate serotonin levels to improve behaviors commonly seen in ASD individuals.²

Objective: The purpose of this study was to explore the link between serotonin and ASD, and how modulation of serotonin levels in the brain via medication can improve ASD phenotypes.

Search Methods: A PubMed database search was utilized to identify literature from 2019 to 2024 with the keywords “ASD”, “Autism Spectrum Disorder”, and “serotonin and ASD”.

Results: Studies indicate that there is an association between levels of available serotonin in the central nervous system (CNS) and ASD. Although there are many causes of ASD, hyperserotonemia and hyposerotonemia give rise to many of the symptoms seen with ASD. In one study measuring the modulation of hyperserotonemia in mouse models for ASD, it was found that mice without the serotonin transporter had enhanced anxiety-like behavior.⁵ Placing these mice on a tryptophan free diet, the precursor amino acid of serotonin, in order to decrease serotonin in the CNS improved social deficits.⁵ In a study done to increase serotonin in the CNS, it was found that using a serotonin receptor agonist (CP-94253) or a drug with the ability to release serotonin in the nucleus accumbens (MDMA) improved social impairments originally seen in ASD mice models.⁶ In a study linking serotonin 1A receptors to anxiety like behaviors, it was found that BTBR mice (ASD models) have disrupted or atypical neural circuits in the amygdala and hippocampus with destabilized serotonin activity that underlies the behavioral phenotypes seen in ASD.⁷ Using the anxiolytic medication, buspirone, research showed that the BTBR mice had reduced serotonin 1A receptor activity in regions of the brain that receive serotonin projections after receiving the medication.⁷ Tracking of neural activity of serotonin showed that in the amygdala and hippocampus, BTBR mice had diminished serotonin 1A receptor response which correlated to buspirone resistance and ASD phenotypes.⁷ Research into the serotonin transporter (SERT) revealed that adults with ASD have lower availability of the transporter in the gray matter and brainstem compared to controls, and this correlates to behavioral phenotypes.⁸ SERT is critical for serotonin clearance, homeostasis, and neurotransmission.⁸ Low SERT availability in the nucleus accumbens of adults with ASD showed correlation to lower performance in all of the behavioral tests and in a number of the executive functioning tests.⁸

Conclusion: ASD is caused by a complex of factors and there is no cure for the disorder. Although the main treatment plan remains behavioral and speech therapy, serotonin modulation through medications may help treat anxiety symptoms associated with ASD. 

Work Cited:

• Takumi T, Tamada K, Hatanaka F, Nakai N, Bolton PF. Behavioral Neuroscience of Autism. Neuroscience & Biobehavioral Reviews. 2020;110:60-76. doi:10.1016/j.neubiorev.2019.04.012
• Higuchi Y, Tada T, Nakachi T, Arakawa H. Serotonergic circuit dysregulation underlying autism-related phenotypes in BTBR mouse model of autism. Neuropharmacology. 2023;237:109634. doi:10.1016/j.neuropharm.2023.109634
• Pourhamzeh M, Moravej FG, Arabi M, et al. The roles of serotonin in neuropsychiatric disorders. Cellular and Molecular Neurobiology. 2021;42(6):1671-1692. doi:10.1007/s10571-021-01064-9
• Al-Dewik NI. Risk factors  diagnosis  prognosis and treatment of autism. Frontiers in Bioscience. 2020;25(9):1682-1717. doi:10.2741/4873
• Tanaka M, Sato A, Kasai S, et al. Brain hyperserotonemia causes autism-relevant social deficits in mice. Molecular Autism. 2018;9(1). doi:10.1186/s13229-018-0243-3
• Walsh JJ, Llorach P, Cardozo Pinto DF, et al. Systemic enhancement of serotonin signaling reverses social deficits in multiple mouse models for ASD. Neuropsychopharmacology. 2021;46(11):2000-2010. doi:10.1038/s41386-021-01091-6
• Higuchi Y, Tada T, Nakachi T, Arakawa H. Serotonergic circuit dysregulation underlying autism-related phenotypes in BTBR mouse model of autism. Neuropharmacology. 2023;237:109634. doi:10.1016/j.neuropharm.2023.109634
• Andersson M, Tangen Ä, Farde L, et al. Serotonin transporter availability in adults with autism—a positron emission tomography study. Molecular Psychiatry. 2020;26(5):1647-1658. doi:10.1038/s41380-020-00868-3