Dataset Information

Extreme enhancement or depletion of serotonin transporter function and serotonin availability in autism spectrum disorder.

ABSTRACT: A variety of human and animal studies support the hypothesis that serotonin (5-hydroxytryptamine or 5-HT) system dysfunction is a contributing factor to the development of autism in some patients. However, many questions remain about how developmental manipulation of various components that influence 5-HT signaling (5-HT synthesis, transport, metabolism) persistently impair social behaviors. This review will summarize key aspects of central 5-HT function important for normal brain development, and review evidence implicating perinatal disruptions in 5-HT signaling in the pathophysiology of autism spectrum disorder. We discuss the importance, and relative dearth, of studies that explore the possible correlation to autism in the interactions between important intrinsic and extrinsic factors that may disrupt 5-HT homeostasis during development. In particular, we focus on exposure to 5-HT transport altering mechanisms such as selective serotonin-reuptake inhibitors or genetic polymorphisms in primary or auxiliary transporters of 5-HT, and how they relate to neurological stores of serotonin and its precursors. A deeper understanding of the many mechanisms by which 5-HT signaling can be disrupted, alone and in concert, may contribute to an improved understanding of the etiologies and heterogeneous nature of this disorder. We postulate that extreme bidirectional perturbations of these factors during development likely compound or synergize to facilitate enduring neurochemical changes resulting in insufficient or excessive 5-HT signaling, that could underlie the persistent behavioral characteristics of autism spectrum disorder.

SUBMITTER: Garbarino VR

PROVIDER: S-EPMC6345621 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Extreme enhancement or depletion of serotonin transporter function and serotonin availability in autism spectrum disorder.

Garbarino Valentina R VR Gilman T Lee TL Daws Lynette C LC Gould Georgianna G GG

Pharmacological research 20180724

A variety of human and animal studies support the hypothesis that serotonin (5-hydroxytryptamine or 5-HT) system dysfunction is a contributing factor to the development of autism in some patients. However, many questions remain about how developmental manipulation of various components that influence 5-HT signaling (5-HT synthesis, transport, metabolism) persistently impair social behaviors. This review will summarize key aspects of central 5-HT function important for normal brain development, a ...[more]

PMID: 30009933

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Project description:BackgroundPatients with autism spectrum disorder (ASD) may have low brain serotonin concentrations as reflected by the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in cerebrospinal fluid (CSF).MethodsWe sequenced the candidate genes SLC6A4 (SERT), SLC29A4 (PMAT), and GCHFR (GFRP), followed by whole exome analysis.ResultsThe known heterozygous p.Gly56Ala mutation in the SLC6A4 gene was equally found in the ASD and control populations. Using a genetic candidate gene approach, we identified, in 8 patients of a cohort of 248 with ASD, a high prevalence (3.2%) of three novel heterozygous non-synonymous mutations within the SLC29A4 plasma membrane monoamine transporter (PMAT) gene, c.86A > G (p.Asp29Gly) in two patients, c.412G > A (p.Ala138Thr) in five patients, and c.978 T > G (p.Asp326Glu) in one patient. Genome analysis of unaffected parents confirmed that these PMAT mutations were not de novo but inherited mutations. Upon analyzing over 15,000 normal control chromosomes, only SLC29A4 c.86A > G was found in 23 alleles (0.14%), while neither c.412G > A (<0.007%) nor c.978 T > G (<0.007%) were observed in all chromosomes analyzed, emphasizing the rareness of the three alterations. Expression of mutations PMAT-p.Ala138Thr and p.Asp326Glu in cellulae revealed significant reduced transport uptake activity towards a variety of substrates including serotonin, dopamine, and 1-methyl-4-phenylpyridinium (MPP(+)), while mutation p.Asp29Gly had reduced transport activity only towards MPP(+). At least two ASD subjects with either the PMAT-Ala138Thr or the PMAT-Asp326Glu mutation with altered serotonin transport activity had, besides low 5HIAA in CSF, elevated serotonin levels in blood and platelets. Moreover, whole exome sequencing revealed additional alterations in these two ASD patients in mainly serotonin-homeostasis genes compared to their non-affected family members.ConclusionsOur findings link mutations in SLC29A4 to the ASD population although not invariably to low brain serotonin. PMAT dysfunction is speculated to raise serotonin prenatally, exerting a negative feedback inhibition through serotonin receptors on development of serotonin networks and local serotonin synthesis. Exome sequencing of serotonin homeostasis genes in two families illustrated more insight in aberrant serotonin signaling in ASD.

Project description:IntroductionHypercholesterolemia is associated with increased inflammation and impaired serotonin neurotransmission, potentially contributing to depressive symptoms. However, the role of statins, particularly pitavastatin, in modulating serotonin transporter (SERT) function within this context remains underexplored. This study aimed to investigate whether pitavastatin counteracts the neurobiological effects of hypercholesterolemia.MethodsLow-density lipoprotein receptor knockout (LDLR-/-) mice on a C57BL/6 background were assigned to three groups: a control group fed a standard chow diet, a group fed a high-fat diet (HFD), and a third group fed a high-fat diet supplemented with pitavastatin (HFD + Pita). We evaluated the effects of HFD with or without pitavastatin on lipid profiles, inflammatory markers, and SERT availability using small-animal positron emission tomography (PET) scans with the radioligand 4-[18F]-ADAM over a 20-week period.ResultsPitavastatin treatment in HFD-fed mice significantly reduced both total cholesterol and LDL cholesterol levels in HFD-fed mice compared to those on HFD alone. Elevated inflammatory markers such as IL-1α, MCP-1/CCL2, and TNF-α in HFD mice were notably decreased in the HFD + Pita group. PET scans showed reduced SERT availability in the brains of HFD mice; however, pitavastatin improved this in brain regions associated with mood regulation, suggesting enhanced serotonin neurotransmission. Additionally, the sucrose preference test showed a trend towards increased preference in the HFD + Pita group compared to the HFD group, indicating a potential reduction in depressive-like behavior.ConclusionOur findings demonstrate that pitavastatin not only lowers cholesterol and reduces inflammation but also enhances SERT availability, suggesting a potential role in alleviating depressive symptoms associated with hypercholesterolemia. These results highlight the multifaceted benefits of pitavastatin, extending beyond its lipid-lowering effects to potentially improving mood regulation and neurotransmitter function.

Dataset Information

Extreme enhancement or depletion of serotonin transporter function and serotonin availability in autism spectrum disorder.

Publications

Extreme enhancement or depletion of serotonin transporter function and serotonin availability in autism spectrum disorder.

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