gms | German Medical Science

60. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie (DGNN)

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie

26. - 28.08.2015, Berlin

Mental retardation in Phenylketonuria: a prominent role of C3 complement

Meeting Abstract

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  • corresponding author presenting/speaker Gabriele Rune - University Medical Center Hamburg-Eppendorf, Institute of Neuroanatomy, Hamburg, Germany
  • Gudrun Schlegel - University Medical Center Hamburg-Eppendorf, Institute of Neuroanatomy, Hamburg, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. 60th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN). Berlin, 26.-28.08.2015. Düsseldorf: German Medical Science GMS Publishing House; 2015. Doc15dgnnP32

doi: 10.3205/15dgnn56, urn:nbn:de:0183-15dgnn565

Veröffentlicht: 25. August 2015

© 2015 Rune et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe



High phenylalanine (phe) concentrations in the brain are considered to account for mental retardation in phenylketonuria (PKU). In the Pahenu2 mouse, an animal model of untreated PKU with similarly elevated levels of phe like in humans, we previously found delayed synaptic pruning and thus increased synaptic density. In order to find out whether delayed synaptic pruning is in fact induced by non-physiological levels of phe, we studied the effects of phenylalanine on synaptic connectivity in hippocampal cultures in this study. In contrast to the findings in the Pahenu2 mouse, synapse density and dendritic length were dramatically reduced in hippocampal slice cultures and dissociated neurons resp. in response to phe treatment. Changes in expression and in phosphorylation of cofilin and reduced activation of the small GTPase Rac1 likely underlie structural alterations. C3 complement expression, which is required for microglia recruitment and activation, and in turn for synaptic pruning was reduced in the Pahenu2 mouse but not in hippocampal slice cultures. Thus, our data show a dual opposing effect of dysfunctional enzyme phenylalanine hydroxylase (PAH) (1) impaired neuronal activity upon elevated levels of phe induces a reduction in C3 complement and as a result impaired microglia activation, delayed synaptic pruning, and thus increased synapse density; (2) impaired neuronal activity upon supraphysiological concentrations of phenylalanine causes loss of synapses and reduced dendritic arborization.