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 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.
Waage-Baudet
H
H
Department of Cell and Developmental Biology, The University of North Carolina, Chapel Hill, NC 27599-7178, USA.
Lauder
J M
JM
Dehart
D B
DB
Kluckman
K
K
Hiller
S
S
Tint
G S
GS
Sulik
K K
KK
D000818:Animals; D001321:Autistic Disorder / Q000209:etiology*; D002452:Cell Count; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005838:Genotype; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics; D011903:Raphe Nuclei / Q000002:abnormalities / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D011985:Receptors, Serotonin / Q000235:genetics* / Q000378:metabolism; D012249:Rhombencephalon / Q000002:abnormalities* / Q000378:metabolism* / Q000473:pathology; D012701:Serotonin / Q000378:metabolism*; D019082:Smith-Lemli-Opitz Syndrome / Q000196:embryology / Q000235:genetics*
D011985:Receptors, Serotonin; D012701:Serotonin; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase