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

Abstract

The Smith-Lemli-Opitz syndrome (SLOS) is a malformation/mental retardation syndrome resulting from an inborn error in 3beta-hydroxysteroid Delta7-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.

Biological activities of 7-dehydrocholesterol-derived oxysterols: implications for Smith-Lemli-Opitz syndrome

“…Even small changes in proliferation rate of neuronal progenitors induced by oxysterols as well as their effect on differentiation of neuronal precursors into specifi c types of neurons would greatly infl uence brain development. For example, in the mouse SLOS model, there is an increase in number of serotonergic neurons and fi bers and changes in the fi ber tract formation (agenesis of corpus callosum and agenesis of hippocampal commissure) ( 75 ). Future studies will show if some of these changes are the result of 7-DHC oxysterol accumulation in the nervous system of the SLOS KO mice.…”

“…Gene expression changes due to defi ciency of Dhcr7 reductase were examined previously in both in vivo and in vitro models ( 40,75 ). Waage-Baudet's ( 75 ) study analyzed gene expression changes in embryonic hindbrain of Dhcr7-defi cient mice, and Korade et al ( 40 ) analyzed gene expression changes in Dhcr7-defi cient Neuro2a cells.…”

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

“…A mouse model related to Smith-Lemli-Optiz syndrome, with a mutation in DHCR7, which encodes the terminal enzyme required for cholesterol biosynthesis, showed alterations in development of the serotonergic system [87], which relate to the common findings of hyperserotonemia in autism [88][89][90]. Oxytocin receptors were found to differ in several brain regions, including specific areas of the piriform, neo, and retrospenial cotices, as well as the hippocampus, in the Reeler mouse [91].…”

Advances in behavioral genetics: mouse models of autism

“…[288][289][290][291] Prenatal Dhcr7-null mice evidence marked increases in measures of serotonin immunoreactivity and a morphological expansion of the serotonergic system. 292 A more viable mouse model for SLOS has been created by generating compound heterozygous animals, carrying a single null Dhcr7 allele and a hypomorphic Dhcr7 T93M allele that reflects a human missense mutation. 293 The combined Dhcr7 alleles in this novel SLOS model appear to be embryonically lethal for approximately 25% of the compound heterozygotes.…”