Handbook of Neurochemistry and Molecular Neurobiology Schizophrenia Abel Lajtha (Ed.) Handbook of Neurochemistry and Molecular Neurobiology Schizophrenia Volume Editors: Daniel C. Javitt and Joshua T. Kantrowitz With62 Figuresand 46Tables Editor AbelLajtha Director CenterforNeurochemistry NathanS.KlineInstituteforPsychiatricResearch 140OldOrangeburgRoad Orangeburg NewYork,10962 USA VolumeEditors DanielJavitt JoshuaKantrowitz Director, Program in Cognitive Neuroscience and NathanKlineInstituteforPsychiatricResearch Schizophrenia 140OldOrangeburgRoad NathanKlineInstituteforPsychiatricResearch Orangeburg 140OldOrangeburgRoad NewYork,10962 Orangeburg USA NewYork,10962 [email protected] USA [email protected] LibraryofCongressControlNumber:2006922553 ISBN:978‐0‐387‐30365‐9 Additionally,thewholesetwillbeavailableuponcompletionunderISBN:978‐0‐387‐35443‐9 TheelectronicversionofthewholesetwillbeavailableunderISBN:978‐0‐387‐30426‐7 TheprintandelectronicbundleofthewholesetwillbeavailableunderISBN:978‐0‐387‐35478‐1 (cid:1)2009SpringerScienceþBusinessMedia,LLC. Allrightsreserved.Thisworkmaynotbetranslatedorcopiedinwholeorinpartwithoutthewrittenpermission ofthepublisher(SpringerScience+BusinessMedia,LLC.,233SpringStreet,NewYork,NY10013,USA), exceptforbriefexcerptsinconnectionwithreviewsorscholarlyanalysis.Useinconnectionwithanyformof informationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar methodologynowknownorhereafterdevelopedisforbidden. Theuseinthispublicationoftradenames,trademarks,servicemarks,andsimilarterms,eveniftheyarenot identifiedassuch,isnottobetakenasanexpressionofopinionastowhetherornottheyaresubjectto proprietaryrights. springer.com Printedonacid‐freepaper SPIN:115310432109–543210 Preface The field of Neuroscience has, in the past decades, undergone an explosive growth and developed very impressiveapproachesandveryexcitingandimportantfindingsonhowthemechanismsinthenervous systemoperate.Inspiteofthesereallysignificantadvances,oureffortstounderstand,cure,andprevent pathologicalchangeshavenotbeensosuccessful.Mentaldiseasetomanymeanslife-longincapacity,which affectsmorepeopleinitsvariousformsandforalongertimethananyotherdisease,andrepresentsamajor financial burden on society, but its elimination remains unfulfilled. We still do not know whether schizophrenia or any other mental disease is a possible manifestation of separate pathologies and if so, whatthebiologicalsimilaritiesanddifferencesbetweenourdiagnosticclassesare.Ofcourseeventemporary helpthatdiminishesthemanifestationsoftheillness,anddiminishestheassociatedsufferingofthespecific hospitalpopulations, isofgreatimportanceandrepresentsacrucialcontribution.Clearly mentalillness affectsnotonlythepatients;itisaburdenonfamiliesandonthewholesociety;itdiminishescontributions tosociety,theproductivelifeandthehappinessofthepatientssufferingfromit. In spite of this, there is a dramatic decrease in hospital population and in incapacitated patients, showing that the field is advancing, and that old dogmas have been replacedbynewones, and we have new hope. The field is constantly advancing: we possess better drugs, better understanding, and more knowledge. Certainly, knowledge of the basic mechanisms that ultimately modulate behavior and its changes,determinepathology,thestructureofreceptors,ofthecells,theinteractionofthecomponents, connections, plasticity, measuring physiological processes, is constantly advancing. With such increasing knowledgecomesourrecognitionofthecomplexitiesofneuralprocesses–especiallytheonesthatgovern behavior, and the ones that are responsible for malfunction. The complexity requires a multifaceted researchapproach;itthereforeworksbestifanumberofsubdivisionscollaborate.Theuseofstructural, imaging,genetic,electrophysiological,pharmacological,andbiologicalexpertise,lookingatinteractionof specificproteinsandofstructuralelementsisneeded.Theknowledgeofsusceptibilityandmuchmoreis nowessentialforabetterunderstandingofthesecomplexmechanisms,which,however,seemmoreand more within reach. Clearly a better understanding will represent a major accomplishment for mankind, withimmensemedical,cultural,humanandeconomicimportance. Thisvolumealsoshowsthatitisimpossibletopredictfromwherethenextadvancesinschizophrenia researchwillcome.Forexample,intheearly1980s,Iledastudylookingattheeffectsofaseriesofamino acidsandaminoacidderivativesonthebehavioraleffectsofphencyclidine.Oftheaminoacidswetested, only glycine and the glycine derivative glycyldodecylamide were found to have a significant behavioral effect.Atthetime,NMDAreceptorshadnotyetbeendescribed,northeinhibitoryeffectsofphencyclidine onNMDAfunction.Certainly,theglycinesiteoftheNMDAcomplexhadnotbeendescribed.Itwouldhave beenimpossibletopredictthataboutadecadelaterthesefindingswouldcontributetothedevelopmentof new classes of medication, such as glycine transport inhibitors, that are currently in clinical trials for schizophrenia, or that much of the work underlying this development would be conducted at my own institution.Hopefully,thecluesthatwillleadtofurtheradvancesintheunderstandingandtreatmentof schizophreniacanbefoundinthisvolume. The multifaceted approach needed for further research development is clearly accomplished in the presentvolumethankstoitsEditors–multidisciplinaryresearchersthemselves.Eachchapterinitself–even thoughitrepresentsanapproachtospecificaspectsofschizophreniadistinctlydifferentfromtheothers– still reflects this need for a complex approach. Each deals with molecular mechanisms, but of different genes,expressingdifferentproteins;eachdealswithstructures,whichderivelargerstructuressuchasthe vi Preface cortex, to smaller structures such as specific receptors, from the relevance of models to the relevance of familystudies.Theyshowthewealthofavailableapproachesandtheexcitingresultsofthiswork.Thesefine reviewsshouldhelpthefieldbypointingoutnotonlywhathasbeenfoundandestablished,butalsowhat else needs to be found. It shows the successes of collaborative studies and the possibilities of such collaborativestudiesinthefuture.Mentaldiseaseisnotonlyamajorburden,italsorepresentsasshown inthesechapters,amajorpossibilitytoapproachandunderstandbehavior,itsfactorsandmechanisms.By pointingoutcurrentknowledge,italsoindicatesthepromiseoffurtherunderstandingandimprovementof availabletherapiesforpatients.Agreatdealhasbeenaccomplished–agreatdealisyettobeaccomplished. Thisvolumeshowsusnotonlytheaccomplishmentsofthepresent,butalsoahopeforourfuture. AbelLajtha Table of Contents Preface . .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. .. v Contributors . . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. . ix NeurochemicalSystems 1.1 CorticalDopamineinSchizophrenia . .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. .. 3 A.Abi-Dargham 1.2 CholinergicMechanismsinSchizophrenia.. .. .. . .. .. .. .. . .. .. .. . .. .. . 17 T.J.Raedler.R.Freedman 1.3 GlutamatergicApproachestotheConceptualizationandTreatment ofSchizophrenia .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. . 39 J.Kantrowitz.D.C.Javitt MolecularTargets 2.1 G72/G30inNeuropsychiatricDisorders . . .. .. .. . .. .. .. .. . .. .. .. . .. .. . 93 J.Shi.L.Cheng.E.S.Gershon.C.Liu 2.2 Dysbindin-1andItsProteinFamily .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 107 With Special Attention to the Potential Role of Dysbindin-1 in Neuronal Functions and the Pathophysiology of Schizophrenia K.Talbot.W.-Y.Ong.D.J.Blake.J.Tang.N.Louneva.G.C.Carlson. S.E.Arnold 2.3 Neuregulin1andSchizophrenia .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 243 Y.-J.J.Chen.L.W.Role.D.A.Talmage 2.4 SynapticVesicleAssociatedProteinsandSchizophrenia . .. . .. .. .. . .. .. 267 H.T.Kao.B.Porton viii TableofContents 2.5 RedoxDysregulationinSchizophrenia:GeneticSusceptibilityand PathophysiologicalMechanisms .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 285 K.Q.Do.P.Bovet.J.H.Cabungcal.P.Conus.R.Gysin.S.Lavoie. P.Steullet.M.Cuenod AnatomicalSystems 3.1 Hippocampus . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 315 S.Heckers 3.2 Early-StageVisualProcessingDeficitsinSchizophrenia .. .. . .. .. .. . .. .. 331 P.D.Butler 3.3 AuditoryCortexAnatomyandAsymmetryinSchizophrenia . .. .. .. . .. .. 353 J.F.Smiley 3.4 TheRoleofPrefrontalAbnormalitiesinSchizophrenia. .. .. . .. .. .. . .. .. 383 M.J.Hoptman.K.A.Nolan ResearchMethodology 4.1 MagneticResonanceSpectroscopy .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 405 P.Milev.S.Miranowski.K.O.Lim 4.2 AlterationsofNeurotransmitterReceptorsinSchizophrenia:Evidence fromPostmortemStudies .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 443 L.V.Kristiansen.R.M.Cowell.M.Biscaia.R.E.McCullumsmith. J.H.Meador-Woodruff 4.3 AnOverviewandCurrentPerspectiveonFamilyStudies ofSchizophrenia .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 493 L.E.DeLisi Behavior 5.1 TheNeurobiologyofNegativeSymptomsandtheDeficitSyndrome. . .. .. 507 B.A.FischerIV.B.Kirkpatrick.W.T.CarpenterJr 5.2 Event-RelatedPotentials(ERPs)intheStudyofSchizophrenia: HowPreclinicalERPStudieshaveContributedtoourUnderstanding ofSchizophrenia .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 525 J.M.Phillips.C.R.Maxwell.R.S.Ehrlichman.S.J.Siegel Index .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .. .. .. . .. .. 545 Contributors AnissaAbi-Dargham WilliamT.Carpenter,Jr. DepartmentsofPsychiatryandRadiology MarylandPsychiatricResearchCenter ColumbiaUniversityCollegeofPhysiciansand P.O.Box21247 Surgeons,NewYork,NY,USA Baltimore,MD21228,USA Email:[email protected] Email:[email protected] StevenE.Arnold Ying-JiunJ.Chen CenterforNeurobiologyandBehavior DepartmentofPathology,CenterforNeurobiologyand DepartmentofPsychiatry,UniversityofPennsylvania BehaviorandtheInstituteofHumanNutrition Philadelphia,PA19104‐3403,USA ColumbiaUniversityandDepartmentofPharmacology StonyBrookUniversity,NY,USA MiguelBiscaia DepartmentofPsychiatryandBehavioralNeurobiology LijunCheng UniversityofAlabamaatBirmingham DepartmentofPsychiatry Birmingham,AL,USA UniversityofChicago DerekJ.Blake Chicago,IL60637,USA DepartmentofPsychologicalMedicine WalesSchoolofMedicine,CardiffUniversity PhilippeConus HeathPark,CardiffCF144XN,UK DepartmentofPsychiatry LausanneUniversityHospital PierreBovet SitedeCery DepartmentofPsychiatry 1008Prilly-Lausanne,Switzerland LausanneUniversityHospital SitedeCery RitaM.Cowell 1008Prilly-Lausanne,Switzerland DepartmentofPsychiatryandBehavioralNeurobiology UniversityofAlabamaatBirmingham PamelaD.Butler Birmingham,AL,USA NathanKlineInstituteforPsychiatricResearch 140OldOrangeburgRd,OrangeburgNY,10962,USA MichelCue´nod Email:[email protected] CenterforPsychiatricNeuroscience DepartmentofPsychiatry JanH.Cabungcal LausanneUniversityHospital CenterforPsychiatricNeuroscience SitedeCery DepartmentofPsychiatry 1008Prilly-Lausanne,Switzerland LausanneUniversityHospital SitedeCery 1008Prilly-Lausanne,Switzerland LynnE.DeLisi DepartmentofPsychiatry GregoryC.Carlson NewYorkUniversity CenterforNeurobiologyandBehavior 650FirstAvenue DepartmentofPsychiatry,UniversityofPennsylvania NewYork,NY10016,USA Philadelphia,PA19104‐3403,USA Email:[email protected] x Contributors KimQ.Do DanielC.Javitt CenterforPsychiatricNeuroscience Director,PrograminCognitiveNeuroscienceand DepartmentofPsychiatry Schizophrenia LausanneUniversityHospital NathanKlineInstituteforPsychiatricResearch SitedeCery 140OldOrangeburgRoad 1008Prilly-Lausanne,Switzerland Orangeburg,NY10962,USA Email:[email protected] Email:[email protected] RichardS.Ehrlichman JoshuaKantrowitz DepartmentofPsychiatry SchizophreniaResearchInstitute UniversityofPennsylvania NathanKlineInstituteforPsychiatricResearch Philadelphia,PA,USA 140OldOrangeburgRoad Orangeburg,NY10962,USA BernardA.Fischer,IV MarylandPsychiatricResearchCenter Hung-TehKao DepartmentofPsychiatry DepartmentofPsychiatryandHumanBehavior UniversityofMarylandSchoolofMedicine BrownUniversity Baltimore,MD,USA DivisionofBiologyandMedicine RobertFreedman 171MeetingStreet,Room187 DepartmentofPsychiatryC249‐32 Providence,RI02912,USA UniversityofColoradoDenverHealthSciencesCenter Email:[email protected] Denver,CO80262,USA Email:[email protected] BrianKirkpatrick DepartmentofPsychiatryandHealthBehavior ElliotS.Gershon MedicalCollegeofGeorgia FoundationsFundProfessorofPsychiatryandHuman Augusta,GA,USA Genetics UniversityofChicago LarsV.Kristiansen 5841S.MarylandAve.MC3077 ResearchLaboratoryforStereologyandNeuroscience Chicago,IL60637,USA BispebjergUniversityHospital Email:[email protected] BispebjergBakke23,IIB 2400CopenhagenNV,Denmark Rene´ Gysin Email:[email protected] CenterforPsychiatricNeuroscience DepartmentofPsychiatry SuzieLavoie LausanneUniversityHospital CenterforPsychiatricNeuroscience SitedeCery DepartmentofPsychiatry 1008Prilly-Lausanne,Switzerland LausanneUniversityHospital SitedeCery StephanHeckers 1008Prilly-Lausanne,Switzerland Chairman,DepartmentofPsychiatry JamesG.BlakemoreProfessorinPsychiatryand KelvinO.Lim ProfessorofRadiology UniversityofMinnesota VanderbiltPsychiatricHospital DepartmentofPsychiatry 160123rdAvenueSouth,Room3060 OfficeofClinicalResearch Nashville,TN37212,USA 717DelawareStreetSE Email:[email protected] Minneapolis,MN55414,USA MatthewJ.Hoptman NathanKlineInstituteforPsychiatricResearch ChunyuLiu 140OldOrangeburgRd.,Bldg.35 DepartmentofPsychiatry Orangeburg,NY10962,USA UniversityofChicago Email:[email protected] Chicago,IL60637,USA Contributors xi NataliaLouneva DivisionofBiologyandMedicine CenterforNeurobiologyandBehavior 171MeetingStreet,Room187 DepartmentofPsychiatry,UniversityofPennsylvania Providence,RI02912,USA Philadelphia,PA19104‐3403,USA ThomasJ.Raedler ChristinaR.Maxwell UniversityofCalgary,FacultyofMedicine DepartmentofPsychiatry Dept.ofPsychiatry,Calgary UniversityofPennsylvania,Philadelphia,PA,USA Alberta,Canada Email:[email protected] RobertE.McCullumsmith DepartmentofPsychiatryandBehavioralNeurobiology LornaW.Role UniversityofAlabamaatBirmingham DepartmentofPathology Birmingham,AL,USA CenterforNeurobiologyandBehaviorandthe InstituteofHumanNutrition JamesH.Meador-Woodruff ColumbiaUniversityandDepartmentofPharmacology DepartmentofPsychiatryandBehavioralNeurobiology StonyBrookUniversity,NY,USA UniversityofAlabamaatBirmingham Birmingham,AL,USA JiajunShi DepartmentofPsychiatry PeterMilev UniversityofChicago UniversityofMinnesota Chicago,IL60637,USA DepartmentofPsychiatry OfficeofClinicalResearch StevenJ.Siegel 717DelawareStreetSE Director,StanleyCenterforExperimentalTherapeutics Minneapolis,MN55414,USA inPsychiatry Email:[email protected] TranslationalResearchLaboratories Rm.2223 SusanMiranowski 125S.31stStreet UniversityofMinnesota PhiladelphiaPA19104,USA DepartmentofPsychiatry Email:[email protected] OfficeofClinicalResearch 717DelawareStreetSE JohnF.Smiley Minneapolis,MN55414,USA PrograminCognitiveNeuroscienceandSchizophrenia NathanKlineInstituteforPsychiatricResearch KarenA.Nolan 140OldOrangeburgNY NathanKlineInstitutefor PsychiatricResearch Orangeburg,NY10962,USA 140OldOrangeburgRd,Bldg.35 Email:[email protected] Orangeburg,NY,10962,USA PascalSteullet Wei-YiOng CenterforPsychiatricNeuroscience DepartmentofAnatomy,NationalUniversityof DepartmentofPsychiatry Singapore,Singapore119260 LausanneUniversityHospital SitedeCery JenniferM.Phillips 1008Prilly-Lausanne,Switzerland DepartmentofPsychology MountSt.Mary’sUniversity KonradTalbot 16300OldEmmitsburgRd. CenterforNeurobiologyandBehavior Emmitsburg,MD21727,USA DepartmentofPsychiatry Email:[email protected] TranslationalResearchLaboratories Room2210 BarbaraPorton 125South31stStreet DepartmentofPsychiatryandHumanBehavior Philadelphia,PA19104‐3403,USA BrownUniversity Email:[email protected]