P4-394: Increased dendritic spine density in adult gerbil hippocampus following oral UMP and DHA supplementation

Abstract

Loss of synaptic functions is a major pathological feature of Alzheimer's disease and related neurocognitive disorders. Developing therapeutic strategies to help prevent the degeneration of synapses may be essential to establish an effective remedial program. Several previous studies suggest that dietary supplementation of membrane phospholipid precursors may provide a way for developing such strategies. To explore this possibility, we previously treated normal adult gerbils by orally administering phospholipid precursors, uridine–5'–monophosphate (UMP, a uridine source) and/or docosahexaenoic acid (DHA) daily for 4 weeks. Animals that received the precursors were found to exhibit significant increases in all of the major brain membrane phospholipids, for example, phosphatidylcholine by 40–45% (Wurtman, Ulus, Cansev, et al., ASBMB abstract, San Francisco, CA, 2006). The precursors also increased expression levels of synaptic proteins, such as PSD–95 (38%) and Synapsin–1 (41%). In this study, we investigated the effect of UMP and DHA on neuronal morphology. Normal adult gerbils were given a diet supplemented with UMP (240 mg uridine/kg) and DHA (300 mg/kg, by gavage) daily for up to 2 weeks. Animals were decapitated, and fixed hippocampal slices were stained with DiI at the end of the treatment. Images of hippocampal neurons were obtained by two–photon microscopy. We found that in animals that received the precursors, dendritic spine density (i.e., the number of spines per unit length of dendrite) was increased significantly in CA1 pyramidal neurons in the hippocampus (27% increase, p = .001 vs. control group given a regular, unsupplemented diet). Our findings suggest that administering a uridine source and DHA can enhance neuronal properties associated with synaptic functions. These findings may be explained in part by enhancement of neuronal membrane synthesis with substrate saturation of enzymes that mediate the precursor incorporation into phosphatidylcholine, and in part by activation of UTP receptors, such as R2Y receptors. Testing of possible therapeutic applications of such precursor supplementation is currently underway.