Role of Cholesterol 24-Hydroxylase in Hippocampal Long-Term Potentiation

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Title: Role of Cholesterol 24-Hydroxylase in Hippocampal Long-Term Potentiation
Author: Ramirez, Denise Marie O'Donnell
Abstract: The mammalian brain contains a disproportionately large percentage of the body's cholesterol , steady -state levels of which are maintained within a narrow range to preserve membrane function . The brain is denied access to circulating lipoproteins by the blood -brain barrier and therefore relies on de novo cholesterol synthesis through the mevalonate pathway to meet the tissue's requirement for this essential lipid . A small amount of brain cholesterol is turned over daily in select neurons by cholesterol 24 -hydroxylase , which catalyzes the production of the membrane -permeable oxysterol 24 (S ) -hydroxycholesterol and represents the major pathway of cholesterol catabolism in this organ . Mice lacking 24 -hydroxylase have a decreased rate of brain cholesterol synthesis and exhibit deficiencies in spatial , associative , and motor learning . Hippocampal slices prepared from these mice are unable to support the induction of long -term potentiation , a type of synaptic strengthening thought to underlie learning and memory . The ability of 24 -hydroxylase knockout slices to exhibit long -term potentiation can be restored by treatment with geranylgeraniol , an isoprenoid end -product of the mevalonate pathway . Mechanistic insight into the role of geranylgeraniol in long -term potentiation has been revealed by calcium imaging studies in neurons cultured from wild -type and 24 -hydroxylase knockout embryos . Neurons from mice lacking 24 -hydroxylase have specific defects in N -methyl -D -aspartate (NMDA ) receptor function , a subtype of ionotropic glutamate receptor essential for long -term potentiation . The subunit composition of NMDA receptors located in various functional pools is normal in 24 -hydroxylase knockout hippocampus , suggesting that geranylgeraniol does not affect expression of NMDA receptors . Localization studies of 24 -hydroxylase show the enzyme is predominantly expressed in the endoplasmic reticulum throughout the soma and dendrites of selected hippocampal , cerebellar , and cortical neurons , consistent with a postsynaptic need for cholesterol turnover in neurons of brain regions important for learning and memory . These findings reveal that cholesterol turnover is important to produce a constant supply of geranylgeraniol , which in turn is necessary for the induction of long -term potentiation and presumably learning in mice .
URI: http : / /hdl .handle .net /2152 .5 /700
Date: 2009-06-18

Citation

Role of Cholesterol 24-Hydroxylase in Hippocampal Long-Term Potentiation. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /700 .

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