Smith-Lemli-Opitz syndrome is an inherited monogenic disorder in which mutations to the 7-dehydrocholesterol (7-DHC) reductase (Dhcr7) gene lead to deficits in cholesterol synthesis. As a result, many patients suffer from gross physiological and neurological deficits. The purpose of this study was to identify a potential abnormal behavioral phenotype in a compound mutant mouse model for Smith-Lemli-Opitz disease (Dhcr7 Δ3-5/T93M ) to further validate the model and to provide potential targets for future therapeutic interventions. We also sought to identify some of the underlying changes in brain function that may be responsible for behavioral differences among groups. The Dhcr7 compound mutant mice were smaller than their single mutant littermates. Both single and compound heterozygous mice made fewer ultrasonic vocalizations when separated from the dam, which may suggest a communication deficit in these animals. Striking increases of the highly oxidizable 7-DHC were observed in the compound mutant mice. 7-Dehydrocholesterol is the precursor to cholesterol and builds up because of decreased function of the mutated Dhcr7 enzyme. Additionally, several differences were noted in the serotonergic system including increased expression of the serotonin transporter and increased uptake of serotonin by isolated synaptosomes. We propose that changes to the oxidative environment during development can have a significant impact on the development of serotonergic function and that this contributes to behavioral differences observed in the mutant mice.
Keywords: SERT; Antioxidant; Dhcr7; Smith-Lemli-Opitz syndrome; development; mouse model; oxysterols; serotonin; ultrasonic vocalizations; vitamin E.
© 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.