Abnormal serotonergic development in a mouse model for the Smith–Lemli–Opitz syndrome: implications for autism

The Smith–Lemli–Opitz syndrome (SLOS) is a malformation/mental retardation syndrome resulting from an inborn error in 3β‐hydroxysteroid Δ7‐reductase (DHCR7), the terminal enzyme required for cholesterol biosynthesis. Using a targeting strategy designed to virtually eliminate Dhcr7 activity, we have created a SLOS mouse model that exhibits commissural deficiencies, hippocampal abnormalities, and hypermorphic development of serotonin (5‐HT) neurons. The latter is of particular interest with respect to current evidence that serotonin plays a significant role in autism spectrum disorders and the recent clinical observation that 50% of SLOS patients present with autistic behavior. Immunohistochemical analyses have revealed a 306% increase in the area of 5‐HT immunoreactivity (5‐HT IR) in the hindbrains of mutant (Dhcr7−/−) mice as compared to age‐matched wild type animals. Amount of 5‐HT IR was measured as total area of IR per histological section. Additionally, a regional increase as high as 15‐fold was observed for the most lateral sagittal hindbrain sections. In Dhcr7−/− mice, an expansion of 5‐HT IR into the ventricular zone and floor plate region was observed. In addition, the rostral and caudal raphe groups exhibited a radial expansion in Dhcr7−/− mice, with 5‐HT IR cells present in locations not seen in wild type mice. This increase in 5‐HT IR appears to represent an increase in total number of 5‐HT neurons and fibers. These observations may help explain the behavioral phenotype seen in SLOS, and provide clues for future therapeutic interventions that utilize pharmacological modulation of the serotonergic system.