gms | German Medical Science

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.