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NIH Annual Report MH002179

NIHAnnualIntramuralResearchReport MH00217927 ReportTitle AnimalModelsOfNeuropsychiatricDisorders 2012FiscalYear October01,2011September30,2012 PrincipalInvestigator JacquelineNCrawleyPhD ResearchOrganization OfficeoftheScientificDirector,NIMH LabStaff DanielleNAbrams BrookeAmberBabineau JenniferMBrielmaier PhilipTylerGastrell DavidKalikhman MichaelNKarras ChicoraFrancesOliver JillSilverman HarrisonASimon SarahMTurner LeukMWoldeyohannes MuYang JamesYuweiZhang CollaboratorsfromotherNIMHorganizations GeorgeDold FrancescoPapaleo CollaboratorsfromotherNIHInstitutes/Centers BronwenMMartinPhD(NIA) StuartMaudsleyPhD(NIA) ExtramuralCollaborators PaulAshwoodPhD(MINDInstitute,UniversityofCaliforniaDavisSchoolofMedicine) OzlemBozdagoPhD(DepartmentofPsychiatry,MountSinaiSchoolofMedicine) JosephDBuxbaumPhD(DepartmentofPsychiatry,MountSinaiSchoolofMedicine) EmanuelDiCiccoBloomMD(DepartmentofNeurology,RobertWoodJohnsonSchoolof Medicine) JacobEllegoodPhD(TorontoCenterforPhenogenomics,HospitalforSickChildren) CatherineLordPhD(DepartmentofPsychology,UniversityofMichigan) JamesMillonigPhD(DepartmentofNeuroscience,RobertWoodJohnsonSchoolofMedicine, UMDNJ) RobertRingPhD((Previous)AutismUnit,PfizerInc.) MustafaSahinMD(ChildrensHospitalDepartmentofNeurology,HarvardUniversity) MariaLuisaScattoniPhD(NeurotoxicologyandNeuroendocrinologySection,IstitutoSuperiori diSanita) MorganShengMBBS,PhD(HHMI,MITandGenentech,SouthSanFrancisco,CA)
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NIH Annual Report MH002179

ElliottSherr(Neurology,UniversityofCaliforniaSanFrancisco) JeremyVeenstraVanderweeleMD(Pharmacology,VanderbiltUniversitySchoolofMedicine) Keywords Autism,Mousemodels,Mousemodelsofautism,Socialbehaviors,Olfactoryandvocalization communicationbehaviors,Repetitivebehaviors,Synapticgenes,Quantitativetraitloci analysis,Drugtreatments,Earlybehavioralinterventions GoalsandObjectives Ouroverarchinggoalistogeneratemousemodelsofneuropsychiatricdisorderswith behavioralphenotypesoptimallyrelevanttocorediagnosticsymptoms.Weemploythese modelstoaddresshypothesesaboutthecausesofmentalillnesses,andtoevaluatethe efficacyofnoveltherapeutics.TheprimaryprojectinFY2011focusedonmousemodelsof autism.Wedesignedmousebehavioraltaskswithfacevaliditytoallthreecategoriesofthe diagnosticsymptomsofautism.Ourassaysincludesocialapproach,juvenileandadult reciprocalsocialinteraction,socialolfactorycuesandresponses,socialultrasonicvocalization cuesandresponses,resistancetochangeinroutineontheMorriswatermaze,andrepetitive selfgrooming.MousemodelsofautismthatwerephenotypedinFY2011withthesetasks includedShank3andEngrailed2mutants,analogoustomutationsinthesesynapticgenesin autisticindividuals,andtheBTBRT+tf/Jinbredstrainthatdemonstratesabnormalities relevanttoallthreediagnosticsymptomsofautism. Theneartermobjectiveistoevaluatehypothesesaboutcandidategenesassociatedwith autism.Thelongtermobjectiveistoapplythesemousemodelspreclinically,toevaluate proposedtreatmentsonreversalandpreventionofsymptomsinthemousemodels.Ongoing intellectualinteractionswithclinicalresearchersintheautismfieldenhancetheclinical relevanceofourtranslationalapproaches.Ongoingevaluationofcompoundsinthepublic domainandfrompharmaceuticalandbiotechnologycompaniesareinprogress,todiscover treatmentsthatreverseand/orpreventautismrelevantbehaviorsingeneticmousemodelsof autismspectrumdisorders. Basedonourbroadexpertiseindevelopingandvalidatingnovelmousebehavioraltasks,we generatedabatteryofbehavioralassayswhichhasbeenextensivelyadoptedbymanyother behavioralneuroscienceandmoleculargeneticslaboratories.Forexample,theautomated threechamberedsocialapproachequipmentdesignedbyDr.CrawleyandbuiltbytheNIMH ResearchServicesBranchiswidelyusednationallyandinternationallyasarapidscreenfor sociabilitydeficitsinmousemodelsofautismandotherneurodevelopmentaldisorders includingRett,FragileX,TuberousSclerosis,schizophrenia,andFragileXsyndromes. InnovativebehavioralphenotypingstrategiesgeneratedbyourLaboratoryofBehavioral Neurosciencehaveloweredthebarrierforextramuralinvestigatorstoexplorethefunctional outcomesoftheirtargetedmutationsofgenesexpressedinthebrain. Summary Autismisaneurodevelopmentaldisorderthataffectsapproximately1%oftheU.S. population.Thecausesofautismspectrumdisordersareunderintenseinvestigation,with strongevidenceforgeneticsubstrates.Lifetimecostsofcaringforautisticindividualsarehigh, bothintermsofa)qualityoflifefortheaffectedindividualsandtheirfamiliesb)financial expensestothefamilies,educationalsystems,andhealthcareagencies. Discoveryofmultiplegenemutations,copynumbervariants,andepigeneticfactorsinpeople withautismhasspurredthedevelopmentofmousemodelswithhomologousmutations. Geneticmanipulationsinmiceofferanoptimizedexperimentalstrategytounderstandthe consequencesofcandidategenemutations.Effectivetreatmentsforthecoresymptomsof autismarecurrentlylimitedtoearlybehavioralinterventions.Discoveryofeffective pharmacologicaltreatmentsrequiresagreaterunderstandingoftheriskgenes,biological mechanisms,andenvironmentalfactorsthatcontributetotheetiologyofautism.Animal modelswithrobustphenotypesrelevanttothediagnosticsymptomsofautismofferan optimizedexperimentalstrategytotesttheefficacyandsafetyofproposedtreatments.
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NIH Annual Report MH002179

OurLaboratoryofBehavioralNeuroscience(LBN)isaninternationalleaderinbehavioral assaysfortransgenicandknockoutmicewithmutationsingenesexpressedinbrainpathways involvedinneuropsychiatricdisorders.Wecollaboratewithalargenumberofmolecular geneticslaboratoriesthatcontributemutantlinesofmicewithmutationsinriskgenesfor autismtoourresearchprogram.ForFY12weconcentratedonwindingdowntheactivitiesof thelaboratoryinpreparationforthedepartureofitsPItoanewpositionatanotheracademic institution. PublicationsGeneratedduringthe2012ReportingPeriod

Orderedbyauthorname.

1. BabineauBA,YangM,CrawleyJN(2012)Mainstreamingmice.Neuropsychopharmacology 37:3001.
[PMID22157866][PMC3238063]

2. BrielmaierJ,MattesonPG,SilvermanJL,SenerthJM,KellyS,GenestineM,MillonigJH, DiCiccoBloomE,CrawleyJN(2012)Autismrelevantsocialabnormalitiesandcognitive deficitsinengrailed2knockoutmice.PLoSOne7:e40914.

[PMID22829897][PMC3400671]

3. MogilJS,SorgeRE,LaCroixFralishML,SmithSB,FortinA,SotocinalSG,RitchieJ,Austin JS,SchorscherPetcuA,MelmedK,CzerminskiJ,BittongRA,MokrisJB,NeubertJK, CampbellCM,EdwardsRR,CampbellJN,CrawleyJN,LariviereWR,WallaceMR,Sternberg WF,BalabanCD,BelferI,FillingimRB(2011)Painsensitivityandvasopressinanalgesia aremediatedbyagenesexenvironmentinteraction.NatNeurosci14:156973.

[PMID22019732][PMC3225498]

4. PapaleoF,YangF,GarciaS,ChenJ,LuB,CrawleyJN,WeinbergerD(2011)Dysbindin1 modulatesprefrontalcorticalactivityandschizophrenialikebehaviorsviadopamineD2 pathways.MolecularPsychiatry,inpress. 5. SilvermanJL,BabineauBA,OliverCF,KarrasMN,CrawleyJN(2012)Influenceof stimulantinducedhyperactivityonsocialapproachintheBTBRmousemodelofautism. Neuropharmacology,inpress(epubaheadofprint).

[PMID22968082][PMC3522798]

6. SilvermanJL,OliverCF,KarrasMN,GastrellPT,CrawleyJN(2012)AMPAKINE enhancementofsocialinteractionintheBTBRmousemodelofautism. Neuropharmacology,inpress(epubaheadofprint).

[PMID22801296][PMC3445667]

7. VeenstraVanderWeeleJ,MullerCL,IwamotoH,SauerJE,OwensWA,ShahCR,CohenJ, MannangattiP,JessenT,ThompsonBJ,YeR,KerrTM,CarneiroAM,CrawleyJN,Sanders BushE,McMahonDG,RamamoorthyS,DawsLC,SutcliffeJS,BlakelyRD(2012)Autism genevariantcauseshyperserotonemia,serotoninreceptorhypersensitivity,social impairmentandrepetitivebehavior.ProcNatlAcadSciUSA109:546974.

[PMID22431635][PMC3325657]

8. YangM,AbramsDN,ZhangJY,WeberMD,KatzAM,ClarkeAM,SilvermanJL,CrawleyJN (2012)LowsociabilityinBTBRT+tf/Jmiceisindependentofpartnerstrain.PhysiolBehav, inpress(epubaheadofprint).

[PMID22245067][PMC3330157]

9. YangM,BozdagiO,ScattoniML,WhrM,RoulletFI,KatzAM,AbramsDN,Kalikhman D,SimonH,WoldeyohannesL,ZhangJY,HarrisMJ,SaxenaR,SilvermanJL,BuxbaumJD, CrawleyJN(2012)Reducedexcitatoryneurotransmissionandmildautismrelevant phenotypesinadolescentshank3nullmutantmice.JNeurosci32:652541.

[PMID22573675][PMC3362928] nidb.nih.gov/search/searchview.taf?ipid=76132 3/4

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NIH Annual Report MH002179

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