Artikel
Synaptic pruning and microglia in Phenylketonuria
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Autoren
Veröffentlicht: | 14. September 2016 |
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Gliederung
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Mutations of the enzyme phenylalanine hydroxylase result in elevated levels of the amino acid phenylalanine (Phe) in blood and cerebrospinal fluid causing the metabolic disorder Phenylketonuria (PKU). In the hippocampus of the mouse model Pahenu2, we found disturbed synaptic pruning resulting in an increased synapse density in adult animals. The increased synapse density was accompanied by reduced activity of microglia and also by reduced mRNA expression of the complement component 3 (C3). In order to determine the direct effect of the amino acid we also tested microglia activity and C3 expression in hippocampal slice cultures after treatment with elevated levels of Phe. Interestingly, Phe had no influence on microglia activity or C3 expression. In a next step we additionally tested phagocytosis capacity of activated microglia under the influence of elevated Phe. Likewise unchanged microglia activity and C3 expression, Phe had no influence on phagocytosis capacity. However, Phe significantly reduced synapse density in hippocampal slice cultures. As a result, reduced microglia activity in the Pahenu2 mouse which ends up in reduced synaptic pruning represents an indirect function of elevated levels of Phe, since Phe reduces synapse density in a microglia independent way in hippocampal slice cultures.