Abstract
The inherited metabolic disease phenylketonuria (PKU) is characterized by increased concentrations of phenylalanine in the blood and brain, and as a consequence neurotransmitter metabolism, white matter, and synapse functioning are affected. A specific nutrient combination (SNC) has been shown to improve synapse formation, morphology and function. This could become an interesting new nutritional approach for PKU. To assess whether treatment with SNC can affect synapses, we treated PKU mice with SNC or an isocaloric control diet and wild-type (WT) mice with an isocaloric control for 12 weeks, starting at postnatal day 31. Immunostaining for post-synaptic density protein 95 (PSD-95), a post-synaptic density marker, was carried out in the hippocampus, striatum and prefrontal cortex. Compared to WT mice on normal chow without SNC, PKU mice on the isocaloric control showed a significant reduction in PSD-95 expression in the hippocampus, specifically in the granular cell layer of the dentate gyrus, with a similar trend seen in the cornus ammonis 1 (CA1) and cornus ammonis 3 (CA3) pyramidal cell layer. No differences were found in the striatum or prefrontal cortex. PKU mice on a diet supplemented with SNC showed improved expression of PSD-95 in the hippocampus. This study gives the first indication that SNC supplementation has a positive effect on hippocampal synaptic deficits in PKU mice.
Highlights
The primary defect in the inherited metabolic disease phenylketonuria (PKU) is the disrupted phenylalanine (Phe) metabolism, caused by mutations in the gene encoding for the hepatic enzyme phenylalanine hydroxylase, which normally converts Phe to tyrosine
To seems the best of our knowledge, thisdeficits is the first report reduced hippocampal expression in this study indicates that specific nutrient combination (SNC) supplementation could have a positive effect on synaptic the PKU mouse model
The most important finding of our study is that SNC supplementation seems to functioning by lessening the reduced expression of PSD‐95 in the hippocampus of C57BL/6 PKU mice dampeninPKU
Summary
The primary defect in the inherited metabolic disease phenylketonuria (PKU) is the disrupted phenylalanine (Phe) metabolism, caused by mutations in the gene encoding for the hepatic enzyme phenylalanine hydroxylase, which normally converts Phe to tyrosine. Increased Phe concentrations disrupt neurotransmitter metabolism, white matter integrity and synapse functioning in PKU patients and in models of PKU [4,5,6,7,8,9,10,11]. Nutrients 2016, 8, 185 and synaptic morphology became evident in Golgi analyses of both PKU patients and PKU mice, showing a decreased number of spines, width of the synaptic cleft and thickness of the post-synaptic density, indicative of reduced synaptic function [5,6,12] These observed morphological abnormalities are corroborated by a decrease in proteins associated with synaptic functioning [9,13,14]. This protein is of interest since it is highly associated with the growth and functioning of dendritic spines and modulates long-term potentiation, a process important for learning and memory [15,16,17])
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