Reduced expression of the serotonin transporter impacts mitochondria in a sexually dimorphic manner

Neuropsychiatric and neurodevelopmental disorders are complex conditions that arise from a variety of interacting genetic and environmental factors. Among these factors, altered serotonergic signalling and mitochondrial dysfunction are strongly implicated, with a growing body of evidence to suggesting that serotonergic signalling is an important regulator of mitochondrial biogenesis. The serotonin transporter (SERT) functions to regulate synaptic 5-HT, and human allelic variants of the serotonin reuptake transporter-linked polymorphic region (5-HTTLPR) are associated with reduced SERT expression and increased susceptibility for developing neuropsychiatric disorders. Using the heterozygous (HET) variant of the SERT knockout rat to model reduced SERT expression, Western blotting was used to measure the abundance of TOMM20 and the complex I protein MT-CO1 as metrics for mitochondrial mass and abundance of respiratory complex IV. Mitochondrial activity was determined by dye reduction. We found sex-based and region-specific differences in mitochondrial mass and activity and that male and females show differing responses to reduced SERT expression. Our findings suggest that the sexually dimorphic differences in serotonergic signalling impact mitochondrial function and that these differences may be important for understanding sex differences in neuropsychiatric and neurodevelopmental disorders.