LAUSR

Background Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive inborn error of cholesterol synthesis caused by mutation of the 7-dehydrocholesterol reductase (DHCR7) gene. This results in abnormal sterol levels, increased 7-dehydrocholesterol and typically decreased cholesterol. Although SLOS has a characteristic physical phenotype, with the most common finding being 2-3 toe syndactyly, there are also multiple behavioral abnormalities. These include cognitive deficits, anxiety, hyper-activity, sleep cycle disturbance, language impairment and autism spectrum behaviors. Methods There are currently two main mouse models of SLOS; a homozygous null, Dhcr7Δ3-5/Δ3-5, and a model combining the null mutation and the common p.T93M missense mutation, Dhcr7Δ3-5/T93M. Unlike the null model, the hypomorphic Dhcr7T93M/Δ3-5 mice can live to adulthood and are therefore suitable for behavioral studies. Anxiety can be measured via multiple commonly used protocols; elevated plus maze (EPM), open field test and assessing burrowing and nesting behavior. Results Although there was variation in all genders and genotypes, overall the Dhcr7T93M/Δ3-5 mice were marginally more likely to have increased burrowing compared to controls. However, this was only significant at 4 months in the overnight study. In contrast, the Nestlet test and EPM are both suggestive of decreased anxiety in the Dhcr7T93M/Δ3-5 mice. Additional histological analysis showed that Dhcr7T93M/Δ3-5 mice tended to have a smaller hippocampus and anterior commissure than age and gender matched controls. Discussion The increased burrowing could be showing the increased anxiety phenotype or hyperactivity, which is also noted in the increased gait speed of the Dhcr7T93M/Δ3-5 mice in the open field test. However, the results of the Nestlet test and EPM are opposite to what is typically observed in patients, therefore these findings are either the result of a secondary defect or suggest that the Dhcr7T93M/Δ3-5 model does not replicate the behavioral traits of patients. The hippocampus is the part of the brain responsible for learning, memory and spatial awareness. As such, the changes seen in the hippocampus could explain the decreased shredding observed in the Nestlet test and the potential delayed learning of the Dhcr7T93M/Δ3-5 mice, observed by the normalization of the behaviors in the EPM and open field tasks. These results are suggestive of subtle structural defects and justify further analysis, particularly using mice with an isogenic background where the differences may be more distinct. As SLOS does not have an optimal treatment pathway, if the results suggested by these tests are accurate, it could help aid the development of therapeutic interventions.