NeurobiologyofDisease38(2010)464–475

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NeurobiologyofDisease

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IncreaseofGABAAreceptor-mediatedtonicinhibitionindentategranulecellsaftertraumaticbraininjury

ZakariaMtchedlishvilia,b, ,EkaLepsveridzed,HongXua,ElenaA.Kharlamova,b,BoLua,KevinM.Kellya,b,c

a

CenterforNeuroscienceResearch,Allegheny-SingerResearchInstitute,AlleghenyGeneralHospital,Pittsburgh,PA,USADepartmentofNeurology,DrexelUniversityCollegeofMedicine,Philadelphia,PA,USAc

DepartmentofNeurobiologyandAnatomy,DrexelUniversityCollegeofMedicine,Philadelphia,PA,USAd

IliaChavchavadzeStateUniversity,FacultyofLifeSciences,Tbilisi,Georgia

b

articleinfoabstract

Traumaticbraininjury(TBI)canresultinalteredinhibitoryneurotransmission,hippocampaldysfunction,andcognitiveimpairments.GABAergicspontaneousandminiatureinhibitorypostsynapticcurrents(sIPSCsandmIPSCs)andtonic(extrasynaptic)wholecellcurrentswererecordedincontrolrathippocampaldentategranulecells(DGCs)andat90daysaftercontrolledcorticalimpact(CCI).At34°C,inCCIDGCs,sIPSCfrequencyandamplitudewereunchanged,whereasmIPSCfrequencywasdecreased(3.10±0.84Hz,n=16,and2.44±0.67Hz,n=7,pb0.05).At23°C,300nMdiazepamincreasedpeakamplitudeofmIPSCsincontrolandCCIDGCs,buttheincreasewas20%higherincontrol(26.81±2.2pAand42.60±1.22pA,n=9,p=0.031)comparedtoCCIDGCs(33.46±2.98pAand46.13±1.09pA,n=10,p=0.047).At34°C,diazepamdidnotprolongdecaytimeconstants(6.59±0.12msand6.62±0.98ms,n=9,p=0.12),thelattersuggestingthatCCIresultedinbenzodiazepine-insensitivepharmacologyinsynapticGABAAreceptors(GABAARs).InCCIDGCs,peakamplitudeofmIPSCswasinhibitedby100μMfurosemide(51.30±0.80pAatbaselineand43.50±5.30pAafterfurosemide,n=5,pb0.001),anoncompetitiveantagonistofGABAARswithanenhancedaf nitytoα4subunit-containingreceptors.PotentiationoftoniccurrentbytheGABAARδsubunit-preferringcompetitiveagonistTHIP(1and3µM)wasincreasedinCCIDGCs(47%and198%)comparedtocontrolDGCs(13%and162%),suggestingthepresenceoflargertoniccurrentinCCIDGCs;THIP(1µM)hadnoeffectonmIPSCs.Takentogether,theseresultsdemonstratealterationsinsynapticandextrasynapticGABAARsinDGCsfollowingCCI.

©2010ElsevierInc.Allrightsreserved.

Articlehistory:

Received11November2009Revised10March2010Accepted10March2010

Availableonline18March2010Keywords:

TraumaticbraininjuryDentategranulecellsGABAAreceptorDiazepamFurosemideTHIP

BicucullinemIPSCs

SynapticcurrentsToniccurrents

Introduction

Cognitivede citsareamongthemostenduringandfrequentlyreportedimpairmentsfollowingtraumaticbraininjury(TBI)(Levinetal.,1979;HallandBornstein,1991),whichcanalsoresultindepression,posttraumaticstressdisorder,andposttraumaticepilepsy(PTE).TBIresultsincomplexpathophysiologythatinvolvescascadesofshort-andlong-termchangesatsubcellularandcellularlevels.ThehippocampusisparticularlyvulnerabletoTBI(DeRidderetal.,2006;Pullelaetal.,2006;Saatmanetal.,2006;Tranetal.,2006;Bonislawskietal.,2007),andcanundergolong-termchangesinitsphysiologicalfunctionandcontributetoalterationsinneurotransmission.GABAAreceptor(GABAAR)-mediatedinhibitioniscriticalforkeepinglocalcircuitexcitatoryactivityunderhomeostaticcontrolandisintimatelyinvolvedintheregulationofcognitiveprocesses,especiallyinlearningandmemory(Castellanoetal.,1993;Collinsonetal.,2002;

Correspondingauthor.AlleghenyGeneralHospital,9J9ST.,320EastNorthAvenue,Pittsburgh,PA15212,USA.Fax:+14123596847.

E-mailaddress:zmtchedl@(Z.Mtchedlishvili).

AvailableonlineonScienceDirect()

.0969-9961/$–seefrontmatter©2010ElsevierInc.Allrightsreserved.doi:

10.1016/j.nbd.2010.03.012

Dasetal.,2004).GABAAR-mediatedsignalingcanbeeitherpotenti-atedordecreasedindifferentanimalmodelsofTBI.Enhancementofpaired-pulseinhibitionwasdescribedinthedentategyrusinthe uidpercussioninjury(FPI)modelinrat(Reevesetal.,1997)andinthecontrolledcorticalimpact(CCI)modelinmouse(Huntetal.,2009).However,ef cacyofGABAwasreportedtobereducedindentategranulecells(DGCs)afterFPIduetofunctionalalterationsinthechloride/potassiumpump(Bonislawskietal.,2007).

Littleisknownaboutlong-termalterationsofpostsynapticGABAARsinDGCsafterheadtrauma.GABAregulatessynchronousneuronaloscillationsthatarecriticalforcognitivefunctionssuchasobjectperception,selectiveattentionandworkingmemory,andspatialmemory(EngelandSinger,2001;BuzsakiandDraguhn,2004),aswellasconsciousness(LlinasandRibary,2001).Thus,disruptionsinGABAergicsignalingafterheadtraumaareverylikelytohaveanimpactonmemoryandcognitivecapacities.PositiveallostericmodulatorsofGABAARsimpairmemoryprocessing(ArolfoandBrioni,1991;Mayoetal.,1993;Kantetal.,1996;Krazemetal.,2001;Johanssonetal.,2002;Silversetal.,2003;Turkmenetal.,2006),whereasGABAARblockersorinverseagonistsoftenpotentiatecognitiveandmemoryperformance(BrioniandMcGaugh,1988;Raffalli-Sebilleetal.,1990;Mayoetal.,