Z.Mtchedlishvilietal./NeurobiologyofDisease38(2010)464–475473

(RudolphandMöhler,2006).Inaddition,our ndingofdecreasedfrequencyofmIPSCs,butnotsIPSCs,mightsuggestdecreasedprobabilityofrelease.SimilarobservationswerereportedinDGCsintheFPImodelofTBI(Tothetal.,1997).

PotentialpathophysiologicalconsequencesofincreasedtonicinhibitionafterCCI

AnincreaseofGABAergictonicinhibitioninDGCs90daysafterCCImaysuggesttheexistenceofanovelmechanismbywhichTBIcontributestotheimpairmentofcognitiveandmemoryfunctions.IthasbeenrecognizedthatincreasedGABAAR-mediatedtonicinhibitionisnegativelycorrelatedwithcognitiveandmemoryfunctions(Caraiscosetal.,2004),whereaspositivemodulatorsofGABAARs,suchasbenzodiazepines,haveamnesiceffectsandadverselyaffectmemory(Maubach,2003).TheroleofGABAergictoniccurrentmediatedbyδsubunit-containingreceptorsinmemoryandcognitionisbeginningtoemerge.Arecent ndingsuggeststhatpotentiationoftonicinhibitioninareaCA3interneuronsmediatedbyδsubunit-containingGABAARscansuppressCA3gamma-frequencyoscillations,whicharecriticalformemoryencodingandretrieval(MannandMody,2009).IncreasedlevelsoftheGABAsynthesizingenzymeGAD67intheprefrontalcortexhasbeencorrelatedwithdeclineofworkingmemory(Koborietal.,2006).InthependulummodelofTBI,impairedspatialmemorywasimprovedafterblockadeofGABAARsandwasattributedtodisinhibitionofpresynapticcholinergictransmission(O'DellandHamm,1995).Takentogether,theseresultssuggestthatconcomitantalterationsintonicandphasicinhibitioninDGCsmayoccurafterTBI.

TBIisamajorriskfactorforthedevelopmentofPTE.Ithasbeensuggestedthatthedentategyrusfunctionsasa“gate”inpreventingthereverberationofexcessiveexcitatorydrivethroughthetrisynapticcircuitformedbythemossy bertoCA3toCA1pyramidalneuron.Breakdownofthisgatecouldbeacriticaleventinthedevelopmentofseizureactivitywithinthetemporallobe(Collinsetal.,1983;StringerandLothman,1989;Heinemannetal.,1992).AlterationsofGABAergicsignalinginDGCsafteranepileptogenicinsulthavebeenlongrecognizedasanimportantpartofawidearrayofmolecular,cellular,andcircuitlevelchangesinthedentategyrus.Althoughwedidnotdocumentseizuresinthe11CCI-injuredanimalsthatunderwentlimitedvideomonitoringbeforesacri ceandelectrophysiologicalstudies,itispossiblethattheseanimalsdemonstratedconvulsiveactivitybeforetheyweremonitoredorhadnon-convulsiveseizures,whichwouldhavebeenundetectablebyvideorecordingswithoutconcomitantEEG.Inaddition,itispossiblethatthe12CCI-injuredanimalsthatwerenotmonitoredmighthavehadundetectedconvulsiveornon-convulsiveseizuresatanypointintimefollowingcorticalimpact.Ifanimalshadbecomeepilepticduringthe90-dayperiodfollowinglesioning,theresultsofthepresentstudywouldneedtobeinterpretedinapotentiallydifferentcontextthanthatofTBI-inducedchangesalone.

Insummary,thepresent ndingssupportdifferentialalterationsoftonicandphasicGABAAR-mediatedinhibitioninDGCsafterasingleepisodeofCCI.Thenetresultofthesedifferentialalterationsisthattheamplitudeoftoniccurrentwasincreasedandbenzodiazepinesensitivityofsynapticreceptorswaslost.These ndingsdemonstrateforthe rsttimethattonicinhibitioncanbealteredafterCCIinDGCs.AdditionalstudiesarerequiredtoelucidatetherelationshipbetweenTBI,increasedtonicinhibitioninthedentategyrus,cognitiveperformance,andthedevelopmentofPTE.Acknowledgments

ThestudywassupportedbyHealthResearchFormulaFundRFA01-07-26,PennsylvaniaDepartmentofHealth(ZM),aResearchGrantfromtheEpilepsyFoundation(ZM),andagrantfromtheGeorgian

NationalScienceScholarsProgram(EL).WethankTeresaM.Hentoszforassistanceinthepreparationofthemanuscript.

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