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1、BehavioralandNeurochemicalCharacterizationofNewMouseModelofHyperphenylalaninemiaTizianaPascucci1,2*1,22,3,GiacomoGiacovazzo,DiegoAndolina,AlessandraAccoto1,21,2,ElenaFiori,1,21,21,245RossellaVentura,CristinaOrsini,DavidConversi,ClaudiaCarducci,VincenzoLeuzz
2、i,StefanoPuglisi-Allegra1,21DipartimentodiPsicologiaandCentro“DanielBovet”,Sapienza-UniversitàdiRoma,Roma,Italy,2FondazioneSantaLucia,IRCCS,Roma,Italy,3DipartimentodiScienzeClinicheApplicateeBiotecnologiche,UniversityofL'Aquila,L'Aquila,Italy,4Dipartimentod
3、iMedicinasperimentaleePatologia,Sapienza-UniversitàdiRoma,Roma,Italy,5DipartimentodiScienzeNeurologiche,PsichiatricheeRiabilitativedell'EtàEvolutiva,UniversitàdiRoma,Roma,ItalyAbstractHyperphenylalaninemia(HPA)referstoallclinicalconditionscharacterizedbyinc
4、reasedamountsofphenylalanineinbloodandothertissues.AccordingtotheirbloodPHEconcentrationsunderafreediet,(PHE)hyperphenylalaninemicpatientsarecommonlyclassifiedintophenotypicsubtypes:classicalphenylketonuria(PKU)(PHE>1200µM/L),mildPKU(PHE600-1200µM/L)andpers
5、istentHPA(PHE120-600µM/L)(normalbloodPHE<120µM/L).ThecurrenttreatmentforhyperphenylalaninemicpatientsisaimedtokeepbloodPHElevelswithinthesaferangeof120-360µM/LthroughaPHE-restricteddiet,difficulttoachieve.Ifuntreated,classicalPKUpresentsvariableneurological
6、andmentalimpairment.However,evenmildlyelevatedbloodPHElevels,duetoabadcompliancetodietarytreatment,producecognitivedeficitsinvolvingtheprefrontalcorticalareas,extremelysensibletoPHE-induceddisturbances.ThedevelopmentofanimalmodelsofdifferentdegreesofHPAisau
7、sefultoolforidentifyingthemetabolicmechanismsunderlyingcognitivedeficitsinducedbyPHE.InthispaperweanalyzedthebehavioralandbiochemicalphenotypesofdifferentformsofHPA(control,mild-HPA,mild-PKUandclassic-PKU),developedonthebaseofplasmaPHEconcentrations.Ourresu
8、ltsdemonstratedthatmicewithdifferentformsofHPApresentdifferentphenotypes,characterizedbyincreasingseverityofbehavioralsymptomsandbrainaminergicdeficitsmovingfrommildHPAtoclassicalPKUforms.Inaddition,ou
