MANIPULATION OF SEROTONIN TRANSMISSION ON BEHAVIOURAL AND NEUROCHEMICAL DEFICITS PROMOTED BY PHENYLKETONURIA

PKU is the most common inborn error of amino acid metabolism among caucasians, with an overall incidence of 1 in 10,000. PHE accumulation is due to impaired function of the enzyme phenylalanine hydroxylase (PAH; EC 1.14.16.1), caused by mutations in the gene that encodes for PAH (PAH; Genbank cDNA Referencem Sequence U49897). The current treatment for the majority of clinical phenotypes, ranging from the mild form of non-PKU (hyperphenylalaninemia) HPA to severe PKU is dietary control of PHE intake. However, the compliance to a rigid low PHE diet is difficult and it is yet unknown when, or even if, the diet can be safely interrupted. In fact, accumulated evidence indicates that even mildly elevated blood Phe levels promote cognitive deficits involving the prefrontal cortex (pFC). These deficits might be explained by the reduced availability of important brain neurotransmitters: biogenic amines. Preliminary data suggest that high PHE blood levels mainly interfere with brain serotoninergic system. Serotonin plays two main roles: as growth regulatory signal in developing brain and as neurotransmitter in the adult brain. We used mouse model of PKU (PAHenu2, ENU2, mutants), which is characterized by severe and generalized cognitive deficits, to evaluate the effects of 5-hydroxytryptophan (5-HTP), a compound that easily increase serotonin levels, on behavioural profile. 5-HTP will be administrated during critical development period to prevent cognitive delay in ENU2 adult mice. Moreover, the drug will be administrated in adult mild hyperphenylalaninemic mice to evaluate its effect on cognitive frontal functions.