Brain cholesterol metabolism is important for learning

Abstract

The brain relies exclusively on de novo synthesis from acetate to fulfill its cholesterol requirement. Turnover of cholesterol within neurons is accomplished by the enzyme cholesterol 24-hydroxylase, a cytochrome P450 that converts cholesterol to the more hydrophilic 24(S)-hydroxycholesterol. This product diffuses out of the brain and is cleared by the liver. We constructed a line of knockout mice in which the cholesterol 24-hydroxylase gene is ablated. Steady state cholesterol content of the brain does not change in the mutant mice but cholesterol synthesis is decreased by 50%, suggesting that cholesterol 24-hydroxylase is responsible for 50% of cholesterol turnover in the brain. The anatomy of the brain in light and electron microscopic analyses does not differ from that of wild type controls. To determine the role of cholesterol 24-hydroxylase in brain function we performed several behavioral tests, including the Morris water maze and cued and contextual fear conditioning tests. Results from these experiments show that the 24-hydroxylase knockout mice have severe deficits in spatial and associative learning and in short and long term memory formation. In vitro studies with hippocampal slices trace these deficits to an impairment of long-term potentiation. Our results suggest that altered cholesterol metabolism in the brain has implications for synaptic plasticity as well as learning and memory. Supported by a grant from the National Institutes of Heart Lung and Blood (HL20948, D.W.R.).