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

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.