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Objective Phenylketonuria (PKU) is caused by a specific mutation of the phenylalanine hydroxylase (PAH) gene. The deficiency of PAH results in high phenylalanine levels (Phe), low tyrosine levels (Tyr), and reduced catecholamine neurotransmitters. The majority of PKU patients, if untreated, develop severe mental retardation. The specific contribution of high Phe and low Tyr levels in mental retardation is largely unknown. In this study, we used organic hippocampal slice cultures in an optimized medium as an adequate culture model to decipher the precise role of high Phe and low Tyr levels on synaptic and glial integrity in PKU. The hippocampus is closely related to learning and memory and reduced catecholamine neurotransmitter levels can be neglected since these neurotransmitters do not derive from the hippocampus. Cultures exposed to physiological concentrations of Phe were compared with cultures exposed to doses of Phe/Tyr, as in the cerebral fluid of PKU patients. Methods Using capillary western blot analysis and immunohistochemistry, followed by quantitative image analysis, we tested the expression of various pre- and postsynaptic proteins (PSD95, synaptopodin, SNAP25, synaptophysin), glial cell markers (GFAP, Iba1, P2Y12, CD68, C3b), and the morphology of glial cells. Results We found a downregulation of the postsynaptic protein PSD95 and the presynaptic protein SNAP25 in the presence of high/low Phe/Tyr levels after 3 weeks, which, then however, recovered after 6 weeks in culture. Furthermore, no change in the expression pattern of glial proteins was observed. Conclusion Our results show that high Phe levels/low Tyr levels alone are unlikely to substantially contribute to mental retardation in PKU. The direct neurotoxic potency of high Phe/low Tyr concentrations is almost negligible since the effects are transient. The transient character in the presence of unchanged levels of high Phe/low Tyr points to a role of reduced catecholamine derivate neurotransmitters, rather than of high Phe/low Tyr levels in PKU.

A culture model for the assessment of phenylalanine neurotoxicity in phenylketonuria