ORCID Profile
0000-0003-0225-3231
Current Organisation
University of Tasmania
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Publisher: Wiley
Date: 18-01-2022
DOI: 10.1002/JNR.25010
Abstract: Neuropsychiatric and neurodevelopmental disorders such as major depressive disorder (MDD) and autism spectrum disorder (ASD) are complex conditions attributed to both genetic and environmental factors. There is a growing body of evidence showing that serotonergic signaling and mitochondrial dysfunction contribute to the pathophysiology of these disorders and are linked as signaling through specific serotonin (5‐HT) receptors drives mitochondrial biogenesis. The serotonin transporter (SERT) is important in these disorders as it regulates synaptic serotonin and therapeutically is the target of selective serotonin reuptake inhibitors which are a major class of anti‐depressant drug. Human allelic variants of the serotonin transporter‐linked polymorphic region (5‐HTTLPR) such as the S/S variant, are associated with reduced SERT expression and increased susceptibility for developing neuropsychiatric disorders. Using a rat model that is haploinsufficient for SERT and displays reduced SERT expression similar to the human S/S variant, we demonstrate that reduced SERT expression modulates mitochondrial copy number and expression of respiratory chain electron transfer components in the brain. In the frontal cortex, genotype‐related trends were opposing for males and females, such that reduced SERT expression led to increased expression of the Complex I subunit mt‐Nd1 in males but reduced expression in females. Our findings suggest that SERT expression and serotonergic signaling have a role in regulating mitochondrial biogenesis and adenosine triphosphate (ATP) production in the brain. We speculate that the sexual dimorphism in mitochondrial abundance and gene expression contributes to the sex bias found in the incidence of neuropsychiatric disorders such as MDD and ASD.
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.NEUBIOREV.2022.104547
Abstract: Serotonergic signalling is implicated in the aetiology of many neuropsychiatric disorders. The serotonin reuptake transporter (SERT) is an important regulator of synaptic serotonin, being an important pharmacological target with genetic variants implicated with risk of developing neuropsychiatric disorders. Animal models have played an important role in understanding the genetic risk and role of SERT function in brain development having highlighted sex differences in incidence, presentation, and treatment efficacy, however, sex bias due to unequal representation of sexes in research remains a significant issue. While more studies are addressing sex as a biological variable this is not reflected in studies using SERT knockout models as the proportion including sex comparisons has declined since 2000. This bias needs to be addressed if research findings from animal studies are to have translation relevance to human conditions.
Publisher: Victoria University of Wellington Library
Date: 2023
Abstract: b Neuropsychiatric and neurodevelopmental disorders such as major depressive disorder (MDD) and autism spectrum disorder (ASD) are complex conditions that can be attributed to a variety of genetic and environmental factors. Altered serotonergic signalling and mitochondrial dysfunction are two factors that are strongly implicated in the pathophysiology of these conditions. Furthermore, there is also a growing body of evidence to suggest a connection between these two factors, as studies have shown that signalling through specific serotonin (5-HT) receptors stimulates mitochondrial biogenesis. The serotonin transporter (SERT) is important in these disorders as it functions to regulate synaptic 5-HT, therefore having a significant influence over serotonergic signalling. Human allelic variants of the serotonin transporter-linked polymorphic region (5-HTTLPR) are associated with reduced SERT expression and increased susceptibility for developing neuropsychiatric disorders. This genetic association is modelled with the heterozygous variant (HET) of the SERT knockout rat, which shows a reduction in SERT expression similar to that of low-expressing human 5 HTTLPR variants. /b This thesis explores mitochondrial biogenesis and respiratory chain activity in the brains of rats with reduced SERT expression, demonstrating that mitochondrial mRNA and protein expression and respiratory chain activity are altered in the brain in a sexually dimorphic manner. While expression and activity are increased in the frontal cortex of male HETs relative to their wild-type counterparts, the opposite trend is seen in females, suggesting that the response to reduced SERT expression differs substantially between males and females. The sex differences identified throughout this thesis are particularly significant as neuropsychiatric and neurodevelopmental disorders differ between males and females in many aspects, with depressive and anxiety disorders being more common in women, and ASD more common in boys. Sex differences are also evident across symptoms, risk factors, and treatment efficacy. Despite this, consideration of sex as a biological variable in preclinical studies of these disorders is poor, and studies continue to restrict their cohorts to male animals. The findings presented in this thesis suggest that the relationship between serotonergic signalling and mitochondrial function may be important for both understanding the pathophysiology of neuropsychiatric and neurodevelopmental disorders, and for inspiring the development of new effective treatments. The prevalence of these disorders is increasing worldwide, significantly impacting the quality of life and life expectancy of those affected, while also generating a substantial economic cost for society. As such, there is a critical need for new research exploring the multitude of genetic and environmental factors associated with these disorders. However, successfully pursuing this line of research is contingent on continued efforts to address sex as a biological variable.
Publisher: Wiley
Date: 16-10-2020
No related grants have been discovered for Bryony Thorne.