Genetic Disruption of Both Tryptophan Hydroxylase Genes Dramatically Reduces Serotonin and Affects Behavior in Models Sensitive to Antidepressants 英文参考文献.docVIP

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Genetic Disruption of Both Tryptophan Hydroxylase Genes Dramatically Reduces Serotonin and Affects Behavior in Models Sensitive to Antidepressants 英文参考文献.doc

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Genetic Disruption of Both Tryptophan Hydroxylase Genes Dramatically Reduces Serotonin and Affects Behavior in Models Sensitive to Antidepressants 英文参考文献

GeneticDisruptionofBothTryptophanHydroxylase GenesDramaticallyReducesSerotoninandAffects BehaviorinModelsSensitivetoAntidepressants KaterinaV.Savelieva*,ShuleiZhao.,VladimirM.Pogorelov.,IndraniRajan,QiYang,EmilyCullinan¤, ThomasH.Lanthorn LexiconPharmaceuticalsIncorporated,TheWoodlands,Texas,UnitedStatesofAmerica Abstract The neurotransmitter serotonin (5-HT) plays an important role in both the peripheral and central nervous systems. The biosynthesisofserotoninisregulatedbytworate-limitingenzymes,tryptophanhydroxylase-1and-2(TPH1andTPH2).We usedagene-targetingapproachtogeneratemicewithselectiveandcompleteeliminationofthetwoknownTPHisoforms. Thisresultedindramaticallyreducedcentral5-HTlevelsinTph2knockout(TPH2KO)andTph1/Tph2doubleknockout(DKO) mice;andsubstantiallyreducedperipheral5-HTlevelsinDKO,butnotTPH2KOmice.Therefore,differentialexpressionof thetwoisoformsofTPHwasreflectedincorrespondingdepletionof5-HTcontentinthebrainandperiphery.Surprisingly, despitetheprominentandevolutionarilyancientrolethat5-HTplaysinbothvertebrateandinvertebratephysiology,none of these mutations resulted in an overt phenotype. TPH2KO and DKO mice were viable and normal in appearance. Behavioral alterations in assays with predictive validity for antidepressants were among the very few phenotypes uncovered.ThesebehavioralchangesweresubtleintheTPH2KOmice;theywereenhancedintheDKOmice.Herein,we confirmfindingsfrompriordescriptionsofTPH1knockoutmiceandpresentthefirstreportedphenotypicevaluationsof Tph2andTph1/Tph2knockoutmice.ThebehavioraleffectsobservedintheTPH2KOandDKOmicestronglyconfirmthe roleof5-HTanditssyntheticenzymesintheetiologyandtreatmentofaffectivedisorders. Citation: Savelieva KV,ZhaoS,PogorelovVM, RajanI,YangQ,etal.(2008)GeneticDisruptionofBoth Tryptophan Hydroxylase GenesDramaticallyReduces SerotoninandAffectsBehaviorinModelsSensitivetoAntidepressants.PLoSONE3(10):e3301.doi:10.1371/journal.pone.0003301 Editor:AlessandroBartolomucci,UniversityofParma,Italy ReceivedJuly16,