P.1.d.013 Prenatal stress increases an anxiety, and alters corticosterone response to 5-HT2A/C agonist in adult female offspring

Abstract

Smith–Lemli–Opitz syndrome (SLOS) is a developmental disorder resulting from mutations to the Dhcr7 gene, which is required for cholesterol synthesis. Patients with SLOS typically exhibit a number of severe behavioral deficits and many are diagnosed with autistic spectrum disorder. Although the molecular pathophysiology underlying behavioral changes in SLOS and autism spectrum disorders is poorly understood, there is evidence for the involvement of the serotonergic system in SLOS and autism in general. Behavioral testing was undertaken to ascertain the basal behavioral differences between Dhcr7-heterozygous (HET) and wild-type control mice and explore the utility of a Dhcr7-HET mouse line in the development of new treatments for this disorder. Dhcr7-HET mice did not differ from wild-type control mice on basic measures of locomotor activity, anxiety and neuromuscular ability. However, female Dhcr7-HET mice at 6 months of age or older were significantly more likely to win on the social dominance tube test against an unfamiliar mouse. Pharmacological testing, using the 5-HT2A agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), showed increased head-twitch response in Dhcr7-HET mice, which was apparent from 6 months of age. No differences were found between the genotypes in testing for 5-HT1A agonist 8-OH-DPAT-induced hypothermia. These data indicate an underlying dysfunction of the 5-HT2A receptors in Dhcr7-HET mice that warrants further investigation to establish how this may relate to behavioral disturbances in human patients carrying Dhcr7 mutations.