Neuropsychiatric disorders such as major depressive disorder (MDD) arise from a complex set of genetic and environmental factors. The serotonin transporter (SERT) is a key regulator of synaptic serotonin (5-HT), and its inhibition is an important pharmacological target for treating MDD. The SERT-linked polymorphic region (5-HTTLPR) contains two major variants (short and long) that have been implicated in modulating susceptibility to MDD by altering the level of expression of SERT. Both variants contain C-rich repeats that conform to consensus i-motif folding sequences. i-Motifs are quadruplex DNA structures that have been proposed to have a role in transcription regulation. With spectroscopic techniques, we demonstrate that both alleles are able to form i-motifs at acidic pH, and at neutral pH under conditions of molecular crowding. This highlights the potential for i-motif formation to contribute to transcriptional regulation of the serotonin transporter, with a potential role in the pathophysiology of neuropsychiatric disorders.
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.
<p><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></p> <p>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. </p> <p>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.</p>
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