Mitochondrial abundance and function in the serotonin transporter knockout model: a sexually dimorphic association

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.

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.