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Review
. 2014 Nov;3(4):110-7.
doi: 10.5582/irdr.2014.01027.

Serotonin dysregulation in Fragile X Syndrome: implications for treatment

Alicia C Hanson  1 , Randi J Hagerman  2
Affiliations
Review

Serotonin dysregulation in Fragile X Syndrome: implications for treatment

Alicia C Hanson et al. Intractable Rare Dis Res. 2014 Nov.

Abstract

Fragile X Syndrome (FXS) is a trinucleotide repeat disorder that results in the silencing of the Fragile X Mental Retardation 1 gene (FMR1), leading to a lack of the FMR1 protein (FMRP). FMRP is an mRNA-binding protein that regulates the translation of hundreds of mRNAs important for synaptic plasticity. Several of these pathways have been identified and have guided the development of targeted treatments for FXS. Here we present evidence that serotonin is dysregulated in FXS and treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline may be beneficial for individuals with FXS, particularly in early childhood.

Keywords: Fragile X Syndrome; fragile X mental retardation protein; selective serotonin reuptake inhibitors; sertraline.

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Figures

Figure 1.
Figure 1.
Tryptophan pathways in patients with autism. The figure illustrates the main intracellular pathways involving tryptophan. The microarray dataset of Boccuto et al. 2013 (consisting of patients with autism) are in blue, genes with increased expression are in red. Genes with statistically significant reduction of expression in patients with autism are underlined. (Note: Figure reprinted and legend adapted from “Decreased tryptophan metabolism in patients with autism spectrum disorders” by Boccuto L, et al., 2013, Molecular autism, 4(1), page 7. Copyright 2013 by BioMed Central. Reprinted with permission.)
Figure 2.
Figure 2.
Neurochemical effects of sertraline therapy in FXS. FMRP, BDNF, serotonin, and dopamine are all dysregulated in patients with FXS. Abnormal levels of FMRP and BDNF in FXS cause atypical dendritic morphology, LTD, LTP, and neurogenesis, all of which have been shown to normalize with serotonin application. Serotonin treatment may also directly benefit patients with FXS as an anxiolytic and by ameliorating defects in LTD, LTP and synaptic architecture. Sertraline may be an especially beneficial SSRI agent for FXS treatment because of its neurprotective effects and positive impact on language development. In addition, sertraline prevents reuptake of dopamine, another neurotransmitter thought to be dysregulated in FXS. Increasing dopamine levels in patients with FXS may help to improve hyperactivity and irregularities in LTP and dendritic morphology.
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