title: Oxidative stress, serotonergic changes and decreased ultrasonic vocalizations in a mouse model of Smith-Lemli-Opitz syndrome.
abstract: 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 (Dhcr7Δ3-5/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.
authors.affiliation: Neuroscience Program, Vanderbilt University, Nashville, TN, USA.
authors.forename: N F
authors.initials: NF
authors.lastname: Sharif
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, TN, USA.|Present address: Department of Pediatrics, Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Korade
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Porter
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: F E
authors.identifier: 0000-0003-1121-0647
authors.initials: FE
authors.lastname: Harrison
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D003684:Dehydrocholesterols / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D019082:Smith-Lemli-Opitz Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000069453:Ultrasonic Waves; D014828:Vocalization, Animal
chemical_list: D003684:Dehydrocholesterols; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; C016705:7-dehydrocholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase
keywords: 
  SERT
  ; Antioxidant; Dhcr7; Smith-Lemli-Opitz syndrome; development; mouse model; oxysterols; serotonin; ultrasonic vocalizations; vitamin E