Genetic variants of MAOB affect serotonin level and specific behavioral attributes to increase autism spectrum disorder (ASD) susceptibility in males

Chakraborti, Barnali; Verma, Deepak; Karmakar, Arijit; Jaiswal, Preeti; Sanyal, Aritrika; Paul, Debarshi; Sinha, Swagata; Singh, Asem Surindro; Guhathakurta, Subhrangshu; Roychowdhury, Anirban; Panda, Chinmoy Kumar; Ghosh, Saurabh; Mohanakumar, Kochupurackal P.; Mukhophadhyay, Kanchan; Rajamma, Usha

doi:10.1016/j.pnpbp.2016.07.001

Cited by 20 publications

(8 citation statements)

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“…Analysis of the two situations reveals that the increased metabolism of 5-HT in ASD females is to compensate for the elevation of 5-HT level in them. Our previous genetic reports reveal association MAO genes with autism, and that also in a gender specific manner (Verma et al, 2014;Chakraborti et al, 2016). We have also shown that 5-HT transporter gene influences ASD (Jaiswal et al, 2015).…”

Section: Discussionsupporting

confidence: 60%

“…Serotonergic functions are regulated at the genetic level and ASD-specific behaviors have genetic effect mediated through serotonergic genes (Muller et al, 2016). Our genetic studies on MAOA (Verma et al, 2014), MAOB (Chakraborti et al, 2016), VMAT2 (unpublished), and ENT4 (unpublished) genes supports this concept, and most genes show gender-bias in association. Multiple etiological factors, to name a few the genetic, epigenetic, neurological factors and clinical heterogeneity make ASD highly complex, that needs to be evaluated through an integrated approach.…”

Section: Discussionsupporting

confidence: 56%

“…When compared between males and females, 5-HT and 5-HIAA levels showed significantly higher level in female controls than in males. 5-HT levels have been shown to be sexually dimorphic and there exists a sex specific enhancement of platelet 5-HT in male ASD cases (Weiss et al, 2005;Chakraborti et al, 2016). Our present study indicates that 5-HT level of hyperserotonemia is 1.8-fold high in females in comparison to male ASDs.…”

Section: Discussionsupporting

confidence: 50%

“…It was deproteinized by adding equal volume of 0.4 M perchloric acid, incubated on ice for 20 min and then centrifuged at 15,000 × g for 15 min at 4 • C to collect clear supernatant. The supernate (10 µl) from both plasma and platelets were injected separately into HPLC-ECD (Bioanalytical Systems, Lafayette, United States) for neurotransmitter analysis (Muralikrishnan and Mohanakumar, 1998;Chakraborti et al, 2016). Here the analytes were separated based on their hydrophobicity using a non-polar stationary phase (C 18 reverse phase column) and a polar mobile phase.…”

Section: Measurement Of Platelet 5-ht Platelet and Plasma 5-hiaamentioning

confidence: 99%

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Gender-Specific Effect of 5-HT and 5-HIAA on Threshold Level of Behavioral Symptoms and Sex-Bias in Prevalence of Autism Spectrum Disorder

et al. 2020

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Platelet hyperserotonemia in a subset of Autism Spectrum Disorder (ASD) probands, efficacy of selective serotonin reuptake inhibitors (SSRIs) in reducing behavioral deficits and gender-bias in normal serotonin (5-hydroxy tryptamine or 5-HT) synthesis suggest disruption in stringent regulation of serotonin metabolism in ASD. Therefore, we investigated the changes in 5-HT and 5-hydroxy indole acetic acid (5-HIAA) in ASD probands to assess its effect on the behavior of male and female probands. ASD cases (n = 215) were examined using childhood autism rating scale (CARS). Platelet 5-HT (104 cases and 26 controls) and platelet/plasma 5-HIAA (73 cases and 17 controls) were estimated using high performance liquid chromatography coupled with electrochemical detector (HPLC-ECD). In male probands, we observed increase in platelet 5-HT content in association with increase in the score for adaptive responses and increase in platelet 5-HIAA levels with concomitant decline in the score for intellectual response. Age did not influence the neurochemical parameters, but imitation, listening responses and nonverbal communication scores decreased with age. Conversely in female probands, plasma 5-HIAA level significantly attenuated with age, when platelet 5-HT content remained unchanged. Interestingly, platelet/plasma 5-HT and plasma 5-HIAA were higher in female controls. Female probands displayed severe autism-associated behaviors. Overall results indicate gender-bias in 5-HT and 5-HIAA regulation, which probably increases the threshold level of ASD phenotypes in the females, thereby affecting ASD prevalence in a sex-specific manner.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionsupporting

confidence: 56%

Section: Discussionsupporting

confidence: 50%

Section: Measurement Of Platelet 5-ht Platelet and Plasma 5-hiaamentioning

confidence: 99%

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Gender-Specific Effect of 5-HT and 5-HIAA on Threshold Level of Behavioral Symptoms and Sex-Bias in Prevalence of Autism Spectrum Disorder

et al. 2020

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“…For instance, monoamine oxidase A (MAO-A), an enzyme that is important for the metabolism of serotonin and norepinephrine, is associated with ASD in a population-based study [ 15 ]. Another population-based association study also indicates that changes in monoamine oxidase B (MAO-B) activity increase ASD risk in males [ 16 ]. Based on those findings, we evaluated the levels of monoamines in Arhgef10 knockout mice to understand the possible roles of Arhgef10 in the serotonergic system.…”

Section: Introductionmentioning

confidence: 99%

Impairment of social behaviors in Arhgef10 knockout mice

Liao

Chen

et al. 2018

Molecular Autism

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BackgroundImpaired social interaction is one of the essential features of autism spectrum disorder (ASD). Our previous copy number variation (CNV) study discovered a novel deleted region associated with ASD. One of the genes included in the deleted region is ARHGEF10. A missense mutation of ARHGEF10 has been reported to be one of the contributing factors in several diseases of the central nervous system. However, the relationship between the loss of ARHGEF10 and the clinical symptoms of ASD is unclear.MethodsWe generated Arhgef10 knockout mice as a model of ASD and characterized the social behavior and the biochemical changes in the brains of the knockout mice.ResultsCompared with their wild-type littermates, the Arhgef10-depleted mice showed social interaction impairment, hyperactivity, and decreased depression-like and anxiety-like behavior. Behavioral measures of learning in the Morris water maze were not affected by Arhgef10 deficiency. Moreover, neurotransmitters including serotonin, norepinephrine, and dopamine were significantly increased in different brain regions of the Arhgef10 knockout mice. In addition, monoamine oxidase A (MAO-A) decreased in several brain regions.ConclusionsThese results suggest that ARHGEF10 is a candidate risk gene for ASD and that the Arhgef10 knockout model could be a tool for studying the mechanisms of neurotransmission in ASD.Trial registrationAnimal studies were approved by the Institutional Animal Care and Use Committee of National Taiwan University (IACUC 20150023). Registered 1 August 2015.Electronic supplementary materialThe online version of this article (10.1186/s13229-018-0197-5) contains supplementary material, which is available to authorized users.

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Blood platelet research in autism spectrum disorders: In search of biomarkers

Padmakumar

Raes

Geet

et al. 2019

Research and Practice in Thrombosis and Haemostasis

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Autism spectrum disorder (ASD) is a clinically heterogeneous neurodevelopmental disorder that is caused by gene‐environment interactions. To improve its diagnosis and treatment, numerous efforts have been undertaken to identify reliable biomarkers for autism. None of them have delivered the holy grail that represents a reproducible, quantifiable, and sensitive biomarker. Though blood platelets are mainly known to prevent bleeding, they also play pivotal roles in cancer, inflammation, and neurological disorders. Platelets could serve as a peripheral biomarker or cellular model for autism as they share common biological and molecular characteristics with neurons. In particular, platelet‐dense granules contain neurotransmitters such as serotonin and gamma‐aminobutyric acid. Molecular players controlling granule formation and secretion are similarly regulated in platelets and neurons. The major platelet integrin receptor αIIbβ3 has recently been linked to ASD as a regulator of serotonin transport. Though many studies revealed associations between platelet markers and ASD, there is an important knowledge gap in linking these markers with autism and explaining the altered platelet phenotypes detected in autism patients. The present review enumerates studies of different biomarkers detected in ASD using platelets and highlights the future needs to bring this research to the next level and advance our understanding of this complex disorder.

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Genetic variants of MAOB affect serotonin level and specific behavioral attributes to increase autism spectrum disorder (ASD) susceptibility in males

Cited by 20 publications

References 56 publications

Gender-Specific Effect of 5-HT and 5-HIAA on Threshold Level of Behavioral Symptoms and Sex-Bias in Prevalence of Autism Spectrum Disorder

Gender-Specific Effect of 5-HT and 5-HIAA on Threshold Level of Behavioral Symptoms and Sex-Bias in Prevalence of Autism Spectrum Disorder

Impairment of social behaviors in Arhgef10 knockout mice

Blood platelet research in autism spectrum disorders: In search of biomarkers

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