Sex bias in the serotonin transporter knockout model: Implications for neuropsychiatric disorder research

Thorne, Bryony N.; Ellenbroek, Bart; Day, Darren J.

doi:10.1016/j.neubiorev.2022.104547

Cited by 9 publications

(12 citation statements)

References 44 publications

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“…Studies in SERT animals have shown sexually dimorphic effects due to reduction of SERT expression. Decreased SERT expression in SERT knock-out mice was associated with region specific reduced receptor expression with greater reduction in females (Li et al 2000 , 2003 ), while genotype-related opposing trends in mitochondrial copy number and expression of the complex I subunit mt-Nd1 expression is seen in male and female SERT Wistar rats (Thorne et al 2022a ). Whether these findings are related to the sex biases seen in addiction behaviours remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Genetics and epigenetics: paternal adolescent ethanol consumption in serotonin transporter knock-out rats and offspring sensitivity to ethanol

et al. 2022

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Rationale Alcohol use disorder (AUD) is shown to have an overall heritability of around 50%. One of the genes associated with AUD is SLC6A4 (solute carrier family 6 member A4) which codes for the serotonin transporter (SERT). The study looked at serotonin dysfunction on ethanol consumption in adolescents and the subsequent intergenerational effects of drinking by using a rat model: SERT+/+ (regular functioning), SERT+/− (50% transporter reduction) and SERT−/− (complete reduction). Objectives We investigated sex and genotype differences in ethanol consumption in SERT knock-out Wistar rats (F0) followed by studying behaviour in the offspring (F1) of the male drinkers to assess effects of paternal alcohol consumption. Methods An intermittent access two-bottle choice paradigm (IA2BC) was used to yield ethanol drinking behaviour in F0 adolescent Wistar rats. The highest drinking males were mated to alcohol-naive females and their offspring were compared with controls. Drinking behaviour (IA2BC) and ethanol-induced motor coordination effects (via rotarod) were measured in the F1s. Results F0 drinking saw no SERT genotype differences in males. However, females consumed higher volumes of ethanol compared to males, with SERT−/− females showing the highest intake. A clearer genotype effect was seen in the F1 animals, with reduction in SERT activity leading to enhanced ethanol intake in both sexes. Importantly, paternal exposure to ethanol significantly reduced the ethanol induced motor side effects in offspring, independent of sex and genotype. Conclusions These indicate a difference in the way genetic factors may act across sexes and suggest the involvement of epigenetic mechanisms in the intergenerational effects of alcohol.

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Section: Discussionmentioning

confidence: 99%

Genetics and epigenetics: paternal adolescent ethanol consumption in serotonin transporter knock-out rats and offspring sensitivity to ethanol

et al. 2022

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“…Nonetheless, these findings of this chapter are particularly compelling as this study is the first to report such major sex differences in this model. Additionally, as the majority of research using the SERT knockout model has been conducted in male animals with little effort to compare sexes when females are included, this study confirms the importance of using sex as a categorical variable in animal research [233]. This highlights an important avenue for future research, especially given the strong sex differences seen in the disorders that the SERT knockout animals model.…”

Section: Genotype-related Differences In the Fc Were Sexually Dimorphicsupporting

confidence: 63%

“…Studies of the SERT knockout model that investigate sex as a biological variable are limited [233]; however, those that compared males and females have identified a variety of interesting sex differences. Initial research identified subtle sex differences in tests for anxiety-and depressive-like behaviour in SERT knockout animals [91].…”

Section: Sex Differences In the Sert Knockout Modelmentioning

confidence: 99%

“…As discussed in the publication included at the beginning of this thesis (Sex bias in the serotonin transporter knockout model: implications for neuropsychiatric disorder research [233]), male bias in biological research is a significant issue. Given that mitochondrial function and SSRI efficacy both show important sex differences [221,224],…”

Section: Publications Were Biased Towards Studying Malesmentioning

confidence: 99%

“…Research shows that the increased susceptibility for depressive and anxiety disorders associated with this allelic variant is more pronounced in women [26] but research on the SERT knockout remains strongly biased towards males. Furthermore, the sex bias in studies researching this model has become progressively worse since the introduction of the model [233].…”

Section: The Literature In This Field Is Biased Towards Malesmentioning

confidence: 99%

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

Thorne¹

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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.

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Sex differences in serotonergic control of rat social behaviour

Poceviciute

Kasperaviciute

Buisas

et al. 2023

Pharmacology Biochemistry and Behavior

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Sex bias in the serotonin transporter knockout model: Implications for neuropsychiatric disorder research

Cited by 9 publications

References 44 publications

Genetics and epigenetics: paternal adolescent ethanol consumption in serotonin transporter knock-out rats and offspring sensitivity to ethanol

Genetics and epigenetics: paternal adolescent ethanol consumption in serotonin transporter knock-out rats and offspring sensitivity to ethanol

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

Sex differences in serotonergic control of rat social behaviour

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