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Abstract
Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, is an essential
component of membrane phosphatides and has been implicated in cognitive functions.
Low levels of circulating or brain DHA are associated with various neurocognitive
disorders including Alzheimer's disease (AD), while laboratory animals, including
animal models of AD, can exhibit improved cognitive ability with a diet enriched in
DHA. Various cellular mechanisms have been proposed for DHA's behavioral effects,
including increases in cellular membrane fluidity, promotion of neurite extension
and inhibition of apoptosis. However, there is little direct evidence that DHA affects
synaptic structure in living animals. Here we show that oral supplementation with
DHA substantially increases the number of dendritic spines in adult gerbil hippocampus,
particularly when animals are co-supplemented with a uridine source, uridine-5'-monophosphate
(UMP), which increases brain levels of the rate-limiting phosphatide precursor CTP.
The increase in dendritic spines (>30%) is accompanied by parallel increases in membrane
phosphatides and in pre- and post-synaptic proteins within the hippocampus. Hence,
oral DHA may promote neuronal membrane synthesis to increase the number of synapses,
particularly when co-administered with UMP. Our findings provide a possible explanation
for the effects of DHA on behavior and also suggest a strategy to treat cognitive
disorders resulting from synapse loss.