Abstract
Smith-Lemli-Opitz (SLO) syndrome is a congenital disorder characterized by severe mental retardation. Patients with SLO lack 7-dehydrocholesterol (7 dH) reductase, which catalyzes the last step of cholesterol synthesis. Administration of an agent that blocks 7 dH cholesterol reductase, BM 15.966 (BM), leads to a biochemical profile which resembles that of SLO patients, i.e., lower plasma, live and brain cholesterol levels accompanied by the appearance of the precursors 7 dH and 8 dH cholesterol. In this article we address the functional consequences of chronic BM treatment on new motor learning by assessing acquisition of the classically conditioned eyeblink response. Just-weaned rats were fed BM by gavage for four months, with half of these rats given exogenous cholesterol during the last two months of BM treatment. Acquisition of the eyeblink response was impaired in BM-treated rats. Impaired acquisition of the eyeblink response was not accompanied by alterations in responsiveness to either the conditioned or unconditioned stimulus. Exogenous cholesterol, a clinically relevant countertreatment, failed to correct for the learning impairment produced by BM treatment. Chronic treatment with a cholesterol synthesis-blocking agent impaired associative learning in just-weaned rats.
Similar content being viewed by others
References
Batta, A. K., Tint, G. S., Shefer, S., Abuelo, D., & Salen, G. (1995). Identification of 8-dehydrocholesterol (cholesta-5,8-dien-3 beta-ol) in patients with Smith-Lemli-Opitz syndrome.Journal of Lipid Research, 36, 705–713.
Baulieu, E. E. (1997). Neurosteroids: of the nervous system, by the nervous system, for the nervous system.Recent Progress in Hormone Research, 52, 1–32.
Blair, H. R. & Martin, J. K. (1966). A syndrome characterized by mental retardation, short stature, craniofacial dysplasia, and genital anomalies occurring in siblings.Journal of Pediatrics, 69, 457–459.
Cohen, M. M. J. & Sulik, K. K. (1992). Perspectives on holoprosencephaly: Part II. Central nervous system, craniofacial anatomy, syndrome commentary, diagnostic approach, and experimental studies.Journal of Craniofacial Genetics and Developmental Biology, 12, 196–244.
Dellair, L. (1969). Syndrome of retardation with urogenital and skeletal anomalies (Smith-Lemli-Optiz syndrome): clinical features and mode of inheritance.Journal of Medical Genetics, 6, 113–120.
Donnai, D., Young, I. D., Owen, W. G., Clark, S. A., Miller, P. F., & Knox, W. F. (1986). The lethal multiple congenital anomaly syndrome of polydactyly, sex reversal, renal hypoplasia, and unilobular lungs.Journal of Medical Genetics, 23, 64–71.
Dvornick, D. & Pill, H. (1968). Effects of long term administration of AY9944, an inhibitor of 7-dehydrocholesterol-7-reductase, on serum and tissue lipids in the rat.Journal of Lipid Research, 9, 587–595.
Garcia, C. A., McGarry, P. A., Voirol, M., & Duncan, C. (1973). Neurological involvement in the Smith-Lemli-Opitz syndrome: clinical and neuropathological findings.Developmental Medicine and Child Neurology, 15, 48–55.
Goldstein, J. L. & Brown, M. S. (1984). Progress in understanding the LDL receptor and HMG-CoA reductase, two membrane proteins that regulate the plasma cholesterol.Journal of Lipid Research, 25, 1450–1461.
Gormezano I, Kehoe EJ, & Marshall BS (1985). Twenty years of classical conditioning research with the rabbit.Progress in Psychobiology and Physiological Psychology, 10, 197–275.
Gottleib, A., Keydar, I., & Epstein, H. T. (1977). Rodent brain growth stages: An analytic review.Biology of the Neonate, 32, 166–76.
Honda, A., Tint, G. S., Salen, G., Batta, A. K., Chen, T. S., & Shefer, S. (1995). Defective conversion of 7-dehydrocholesterol to cholesterol in cultured skin fibroblasts from Smith-Lemli-Opitz syndrome homozygotes.Journal of Lipid Research 36, 1595–1601.
Irons, M., Elias, E. R., Salen, G., Tint, G. S., & Batta, A. K. (1993). Defective cholesterol biosynthesis in Smith-Lemli-Optiz syndrome [letter].Lancet, 341, 1414.
Robel, P., Young, J., Corpéchot, C., Mayo, W., Perché, F., Haug, M., Simon, H., & Baulien, E. E. (1995). Biosynthesis and assay of neurosteroids in rats and mice: functional correlates.Journal of Steroid Biochemistry and Molecular Biology, 53, 355–360.
Servatius, R. J. & Shors, T. J. (1994). Exposure to inescapable stress persistently facilitates associative and nonassociative learning in rats.Behavioral Neuroscience, 108, 1101–1106.
Shefer, S., Salen, G., Batta, A. K., Honda, A., Tint, G. S., Irons, M., Elias, E. R., Chen, T. C., & Holick, M. F. (1995). Markedly inhibited 7-dehydrocholesterol-delta 7-reductase activity in liver microsomes from Smith-Lemli-Optiz homozygotes.Journal of Clinical Investigation, 96, 1779–1785.
Shefer, S., Salen, G., Nguyen, L., Batta, A. K., Packin, V., Tint, G. S., & Hauser, S. (1988). Competitive inhibition of bile acid synthesis by endogenous cholestanol and sitosterol in sitosterolemia with xanthomatosis. Effect on cholesterol 7 alpha-hydroxylase.Journal of Clinical Investigation, 82, 1833–1839.
Smith, D. W., Lemli, L., & Opitz, J. M. (1964). A newly recognized syndrome of multiple congenital anomalies.Journal of Pediatrics, 64, 210–217.
Smith, M. E. & Hasinoff, C. M. (1970). Inhibitors of cholesterol synthesis and myelin formation.Lipids, 5, 665–671.
Stanton, M. E. & Freeman, J. H. J. (1994). Eyeblink conditioning in the infant rat: an animal model of learning in developmental neurotoxicology.Environmental Health Perspectives, 102, 131–139.
Stanton, M. E., Freeman, J. H. J., & Skelton, R. W. (1992). Eyeblink conditioning in the developing rat.Behavioral Neuroscience, 106, 657–665.
Stanton, M. E. & Goodlett, C. R. (1998). Neonatal ethanol exposure impairs eyeblink conditioning in weanling rats.Alcoholism: Clinical and Experimental Research, 22, 270–275.
Thompson, E. & Baraitser, M. (1986). An autosomal recessive mental retardation syndrome with hepatic fibrosis and renal cysts.American Journal of Medical Genetics, 24, 151–158.
Thompson, R. F., Bao, S., Chen, L., Cipriano, B. D., Grethe, J. S., Kim, J. J., Thompson, J. K., Tracy, J. A., Weninger, M. S., & Krupa, D. J. (1997). Associative learning.International Review of Neurobiology, 41, 151–189.
Tint, G. S., Irons, M., Elias, E. R., Batta, A. K., Frieden, R., Chen, T. S., & Salen, G. (1994). Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome [see comments].New England Journal of Medicine, 330, 107–113.
Xu, G., Salen, G., Shefer, S., Ness, G. C., Chen, T. S., Zhao, Z., Salen, L., & Tint, G. S. (1995). Treatment of the cholesterol biosynthetic defect in Smith-Lemli-Optiz syndrome reproduced in rat by BM 15.766.Gastroenterology 109, 1301–1307.
Xu, G., Salen, G., Shefer, S., Ness, G. C., Chen, T. S., Zhao, Z., & Tint, G. S. (1995). Reproducing abnormal cholesterol biosynthesis as seen in the Smith-Lemli-Optiz syndrome by inhibiting the conversion of 7-dehydrocholesterol to cholesterol in rats [see comments].Journal of Clinical Investigation, 95, 76–81.
Xu, G., Servatius, R. J., Shefer, S., Tint, G. S., OBrien, W. T., Batta, A. K., & Salen, G. (1998). Relationship between abnormal cholesterol synthesis and retarded learning in rats.Metabolism, 47, 878–882.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
O’Brien, W.T., Xu, G., Tint, G.S. et al. Blocking cholesterol synthesis impairs acquisition of the classically conditioned eyeblink response. Integrative Physiological and Behavioral Science 35, 120–131 (2000). https://doi.org/10.1007/BF02688771
Issue Date:
DOI: https://doi.org/10.1007/BF02688771