ALTERED SYNAPTIC PLASTICITY IN A MOUSE MODEL OF GENETIC MENTAL RETARDATION SYNDROME

Phenylketonuria (PKU) is a genetic disease caused by mutation in the gene encoding for the enzyme phenylalanine hydroxylase. PKU is characterized by high PHE plasma levels and by severe mental delay due to dysfunctions in the prefrontal cortex (pFC), an area highly sensitive to PHE accumulation. The genetic model of PKU, ENU2 mice, represents a valid tool to identify the molecular mechanisms underlying PKU cognitive delay. It is known that serotonin (5-HT) plays a crucial role in regulating neuronal maturational events during early postnatal period, including spine morphology in pFC. Our previous data showed that 5-HT is the most affected amine in PKU brain, suggesting a role for 5-HT in the PHE-induced cognitive dysfunctions. In order to link 5-HT brain deficits with pFC dysfunction in ENU2 mice, we have analyzed expression of 5-HT2A receptors and synaptic cell adhesion molecules (Neuroligins), acting as organizers in the recruitment of neurotransmitter receptors at the synapse. We observed higher messenger levels of cortical 5-HT2A receptors in ENU2 compared with WT mice. Analysis of protein levels for the NLGNs revealed significant reduced levels in ENU2 compared with WT. Furthermore, ENU2 mice showed higher NLGN1 and 3 and lower NLGN2 messenger levels in comparison with WT in pFC. Our data support the hypothesis of Kaufmann and Moser that a primary genetic deficit leads to alterations of synaptic proteins that regulate dendritic spine functions. Further characterization of synaptic components involved in pFC development might open to new therapeutic strategies for neurodevelopmental diseases associated to cognitive delay.