Hippocampal ether-a-go-go1 potassium channels blockade: Effects in the startle reflex and prepulse inhibition

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Neuroscience

Letters

j o ur na l h o me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / n e u l e t

Hippocampal

ether-à-go-go1

potassium

channels

blockade:

Effects

in

the

startle

reflex

and

prepulse

inhibition

A.C.

Issy

a,1

,

J.R.

Fonseca

b,1

,

L.A.

Pardo

c

,

W. Stühmer

c

,

E.A.

Del

Bel

a,∗

a_Department_of_Morphology_Physiology_and_Basic_Pathology,_University_of_São_Paulo_(USP),_Dental_School_of_Ribeirão_Preto,_Brazil b_Federal_University_of_São_Paulo_(UNIFESP),_Brazil

c_Department_of_Molecular_Biology_of_Neuronal_Signals,_Max-Planck_Institute_of_Experimental_Medicine,_Gottingen,_Germany

h

i

g

h

l

i

g

h

t

s

•Eag1K+_channels_blockade_in_the_dentate_gyrus_of_the_hippocampus_did_not_modify_{apomorphine-disruptive}_effects_in_the_PPI.

•DentategyrussurgeryinducingdecreasedstartleresponsewasrestoredbytheEag1antibody. •TheroleofEag1K+_channels_in_the_startle_response_merits_further_{investigation.}

a

r

t

i

c

l

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n

f

o

Articlehistory:

Received6August2013 Receivedinrevisedform 13November2013 Accepted16November2013

Keywords:

Dopamine Prepulseinhibition Schizophrenia Eag1 Kv10.1 Startlereflex

a

b

s

t

r

a

c

t

Recently,ourgroupdescribedtheether-à-go-go1(Eag1)voltage-gatedpotassium(K+₎_channel_(Kv10.1) expressioninthedopaminergiccellsindicatingthatthesechannelsarepartofthediversifiedgroupofion channelsrelatedtodopaminergicneuronsfunction.Theincreaseofdopamineneurotransmissioninduces areductionintheprepulseinhibition(PPI)oftheacousticstartlereflexinrodents,whichisareliable indexofsensorimotorgatingdeficits.ThePPIresponsehasbeenreportedtobeabnormallyreducedin schizophreniapatients.TheroleofEag1K+_channels_in_the_PPI_reaction_had_not_been_revealed_until_now, albeitthesingulardistributionofEag1inthedentategyrusofthehippocampusandthehippocampal regulationofthestartlereflexandPPI.TheaimofthisworkwastoinvestigateifEag1blockadeon hippocampusmodifiesthePPI-disruptiveeffectsofapomorphineinWistarrats.Bilateralinjectionof anti-Eag1single-chainantibodyintothedentategyrusofhippocampusdidnotmodify apomorphine-disruptiveeffectsinthePPIresponse.However,Eag1antibodycompletelyrestoredthestartleamplitude decreaserevealedafterdentategyrussurgery.Thesepotentiallybiologicalimportantphenomenonmerits furtherinvestigationregardingtheroleofEag1K+_channels,_mainly,_on_startle_reflex_modulation,_since thephysiologicalroleofthesechannelsremainobscure.

1. Introduction

Ether-à-go-go-related gene (ERG) potassium (K+₎ _channel _is

mainlyexpressedinthehumanandrodentsadultbrain[23,24].

ERGK+_channels_belong_to_a_superfamily_of_{voltage-activated}_K+

channelsencoded by three distinct gene subfamilies, including

ether-à-go-go (eag), ether-à-go-go-like (elk), and ether-à-go-go -related(erg)genes[8,42].Amongthem,theEagK+_channel_appears

tobetheonlymainlyneuron-specificand localizedtosynapses

∗Correspondingauthorat: DepartmentofMorphologyPhysiologyandBasic Pathology,UniversityofSãoPaulo,DentalSchoolofRibeirãoPreto,Centerfor Inter-disciplinaryResearchonAppliedNeurosciences(NAPNA),14049-904,Brazil. Tel.:+551636024047;fax:+551636330999.

E-mailaddress:eadelbel@forp.usp.br(E.A.DelBel).

1 _These_authors_contributed_equally_to_this_work.

[18]. Eag K+ _channel _is _represented_by _the _Eag1 _gene _(KCNH1,

Kv10.1)[26,42]andEag2 (KCNH5,Kv10.2)[19,23].HighestEag1

geneexpressionisfoundinthecerebralcortex,hippocampus, cere-bellumandhypothalamusofhumanandrat,whichgreatlyoverlaps withEag1proteinexpression[24].However,thefunctionofEag1 K+_channels_in_the_central_nervous_system_is_still_unknown_[26,27]_.

ItwassuggestedthatthelateraldiffusionofEag1ionchannelsacts

asadynamicalmechanismtoaccruethesechannelstothe

synap-ticterminals,wheretheyshouldplaya pivotalroleforsynaptic functionandplasticity[11].TheexpressionoftheEag1K+_channel

ishighinthenigrostriatalpathwayanditisco-localizedwiththe dopaminergiccells[7].Thisdatasuggeststhatthesechannelsmay wellparticipateinthephysiologyofthedopaminergicsystem[7]. Sensorimotorgatingistheabilitytogateoutirrelevantstimuli, anormalcentralinhibitoryprocessesexpression,anditsabilitycan beaccessedthroughprepulseinhibition(PPI)inhumans[2,29,38]

and rodents [3,36,37]. Schizophrenia patients exhibit heritable

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postmortemhistological,morphometricandgeneticanalyses[14]. SpecificevidenceforthehippocampalregulationofPPIcomesfrom experimentalanimal studies [5,39]. Recently, K+ _channels _have

beenproposedtoplayaroleinthemechanismsofneuralplasticity whicharealteredinvariouspsychiatricdisorders,especiallyin hip-pocampus[16].Thedentategyrusofthehippocampusactsasthe “gatekeeper”orthe“filter”ofthehippocampalfunction[10].Ithas

beendescribedthatdopaminemodulatestheactivityofnew

den-tategranulecellsinthedentategyrus[25].Also,dopamineactsas agateonthedirectcorticalinputtothehippocampus,modulating synapticplasticityandinformationflowinafrequency-dependent manner[17].In thiscontext,Eag1K+ _channel_expression_in_the

dentategyrusofhippocampalneurons[7]becomesinteresting. Becauseof thelack ofspecific pharmacologicalinstruments,

Eag1monoclonalantibodymayprovideanattractivetoolto

elu-cidatethe functional role of this channel in mammalian brain

[24].Monoclonalantibodiesrepresentastrategytogeneratehighly selectiveinhibitorsagainstcellsurfacemolecules,enablinga spe-cificantigentobedistinguishedfromitsclosehomologues[12,31]. AspecificEag1antibodywasvalidatedanddescribedasthefirst monoclonalantibodythatselectivelyinhibitsaK+_current_in_intact

cells[12].Takingadvantageofthespecificityoftherecombinant anti-Eag1single-chainantibody,andthesingulardistributionof Eag1inthehippocampus(Fig.1)[7]weinvestigatetheeffectsof Eag1antibodymicroinjectionintothedentategyrusofratsafter

systemicapomorphinetreatment.

2. Materialsandmethods

2.1. Animals

Male Wistarrats (n=11; 250–300g) were used. The

experi-mentalprotocolfollowedtheguidelinesforthecareanduseof

mammalsinNeuroscienceand BehavioralResearch(ILAR, USA).

Rats werehoused fourper cage, undercontrolled temperature

(23±1◦_C)_and_light/dark_cycle_(12–12_h;_lights_on_at₀₆₀₀_hours)

withfoodandwaterconstantlyavailable.Testswereperformedin thelightphase.

2.2. Drugs

Apomorphine(Sigma–Aldrich,Germany)wasdissolvedin

dis-tilledwaterwith0.1%ascorbicacidandinjectedsubcutaneously (s.c.;0.5mg/kg)at 1ml/kg.Eag1-specific recombinantanti-Eag1 single-chainantibody(1␮g/1␮lofwaterRNAsefree)was

bilat-erallyinjectedwith30 gaugeneedles(16mm)intothedentate

gyrusatavolumeof0.5␮Ldeliveredover60susingamicrodrive

injectionpump.

test(post-surgicalanalyses)beforeapomorphinetreatment.

2.4. Surgery

Rats were anesthetized with ketamine/xylazine (10:7,

100mg/kg; intraperitoneal) and placed in a stereotaxic

appa-ratus.Stainless steel guidecannulaewere bilaterallyimplanted

3mmabovetheinjectionsitewithinthedentategyrus

(antero-posterior,−4mm;lateral,±2.6mm;dorso-ventral,−2.1mm)[28].

Theguidecannulaewerekeptunobstructedbydummystylets.

2.5. Experimentaldesign

Aftersurgeryforbilaterallyhippocampuscannulae implanta-tionallratsshowedasignificantdecreaseoftheirstartleamplitude (comparedtopre-testcondition).Animalsweretestedrepeatedly (pre-test,post-surgicalapomorphine,andapomorphine+Eag1K+

channelantibody)withaminimumintervalof4days,with excep-tionofthepostsurgicaltest.PPIdisruptionwasinducedbyacute apomorphinetreatment.Microinjectionoftheanti-Eag1K+

chan-nelantibodybilaterallyinthedentategyrusofhippocampuswas

conducted20minaftertheapomorphinetreatment.Tworatswere

notincludedinthebehavioralanalyses(Fig.2).

2.6. Statisticalanalyses

The acoustic startle response to pulse alone and to

pre-pulse+pulse was analyzed by repeated measures analysis of

variance(RM-ANOVA)withstimuli(fourlevels:pulse;81 or73

or69dBprepulse+pulse)asawithin-subjectsfactorandcondition (preorpost-surgicalorpharmacologicaltreatment;fourlevels)as

between-subjectsfactors.Forthemean%PPI,RM-ANOVAwas

con-ductedwithintensityofprepulse(threelevels)asawithin-subject factor,andconditionasabetween-subjectsfactor.Inthecaseof

significantmaineffectstheRM-ANOVAwasfollowedbyDuncan’s

testforposthoccomparisons(P<0.05).

3. Results

3.1. Startleamplitude

Wefoundasignificantmaineffectofstimuli(F(3,96)=13.017;

P=0.000)andcondition(F(3,32)=6.48;P=0.001),butnota signif-icantinteractionbetweenstimuliand condition(F(9,96)=1.866;

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Fig.1. PhotomicrographsAandBshowingEag1immunoreactivityintherathippocampus.Thedetectionsystem(NBT/BCIP)producedanintensebluecolormainlyinthe cellbodies.

thestartleamplitude wassignificantlyincreased (bringto nor-mal)comparedwiththepost-surgicalcondition(posthocDuncan;

P<0.05;Fig.3).Inthe81and73dBprepulse+pulsetrialsthestartle

magnitudewassignificantlowerthantherespectivestimulusof

thepre-testcondition.However,importantly,thestartle

ampli-tudetothe pulsewashigherthan thestartleamplitudetothe

prepulse+pulse(withallprepulseintensities)inthepostsurgical condition(Fig.3).

3.2. Prepulseinhibition

There was a significant effect of condition (F(3,32)=4.10;

P=0.014),butnotofprepulseintensity(F(2,64)=0.185;P=0.831)

or an interaction between prepulse intensity and condition

Fig. 2.Hematoxilin-eosin representative histological sectionand cannulae-tip placementsschemawithinthedentategyrusofhippocampus.Injectionneedletips locationwithinthedentategyrusofhippocampuswasdeterminedaccordingtothe standardizedplates–Bregma−2.06;interaural1.74mm[28].Twoanimalswithin cannulaeinsertionsoutsidethedentategyruswerenotincludedindataanalyses.

(F(6,64)=1.105;P=0.369).Systemictreatmentwithapomorphine inducedsignificantPPIdisruption.Eag1antibodyinjected bilat-erallyintothedentategyrusdidnotmodifythiseffect(posthoc Duncan;P<0.05;Fig.4).PPIonpost-surgical conditionwasnot differenttothepre-test(datanotshown).

4. Discussion

DopaminesystemappearstobecriticalconnectedtothePPI

modulation[36].PPIresponsemaybedisruptedinschizophrenia patients[2,36],despitethefactthatPPIimpairmentisobservedin severalotherpsychiatricdisorders[2,9].Clearly,thePPIdeficitthat isexperimentallyinduceddoesnotconstituteananimalmodelof schizophreniapersebutappearstoprovideanapplicablemodelof sensorimotorgatingdeficit[9,25].Theantipsychoticdrugsusedto

treatschizophreniasymptomssharethepharmacologicalproperty

ofdopamineD2receptorantagonism[20].Itwassuggested, how-ever,thatthetherapeuticactionofantipsychoticdrugscouldbein additiondependentonthepresynapticERGK+_channel_inhibition

[6,32,40].WeinvestigatetheabilityofanEag1K+_channel_antibody

microinjectedintothedentategyrusofhippocampusto

attenu-atetheapomorphine-inducedPPIdisruption.Bilateralinjectionof

Fig.3.EffectsofEag1K+_channels_antibody_on_the_startle_amplitude._Animals

showedsignificantdecreaseintheirstartleamplitudetopulsealoneaftersurgery. Apomorphinetreatmentinducedanincreaseinthestartleresponse,butthiseffect wasnotstatisticallysignificant.TheEag1K+_channels_antibody_bilaterally_injected_in

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Fig.4. EffectsofEag1K+ _channels_antibody_in_the_PPI_disruption_induced_by

apomorphine.Eag1K+_channels_antibody_bilaterally_injected_on_dentate_gyrus_of

hippocampusdidnotmodifythePPI-disruptiveeffectofapomorphine(prepulse intensitiesof73and81dB).*P<0.05comparedwithpost-surgicalcondition.Data representmeans±SEM.RM-ANOVA,posthocDuncan(P<0.05;n=9).

Eag1antibody(0.5␮gdatanotshown;or1.0␮g)intothedentate

gyrusdidnotmodifyapomorphine-disruptiveeffectsinthePPI,but reversedthedecreasedstartleamplitudemeasuredaftersurgery.

NophysiologicalfunctionfortheEag1K+_channels_in_the_central

nervoussystemhasbeenreportedsofarformammals.Recently,

nodifferenceinthe PPIdisruptioninducedby apomorphine in

Eag1knockoutanimalswasfound,corroboratingwithourresults

[41]. However, these authors demonstrate that Eag1 knockout

mice(Kv10.1−/−) showan increased reactivity to apomorphine

treatmentinthePPItestafteramphetaminesensitization,anda significantincreaseintheresponsivenesstothehaloperidolinthe catalepsytest.TheauthorssuggestedthatKv10.1−/−miceshowa

hyperreactivityofthedopaminergicsystem,oradecreased

den-sity/numberofthedopaminergicreceptors[41].

Itwasimpossibletodisclosethereasonfordecreasingstartle

amplitudeafterthehippocampalcannulaeimplantation.Despite

thefact that startle reflexis sensitiveto habituation, and may

reflect hearing loss, these do not appear the reasons for the

startledecrease.Zhangandco-workersconductedseveralstudies

usinganextensivenumberofdrug-freeratswithdorsalor

ven-tralhippocampal-cannulation[1,44–46],buttheseauthorsdidnot describeanystartlerefleximpairment. Contrasting, ithasbeen reportedtheimpactofdifferentmanipulationsonventralor dor-salhippocampusinthestartlereactivity[45,46].Inaddition,Zhang andco-workers[46]suggestedthattheseeffectsinthestartle

reac-tivitymaybemediatedthroughthehippocampalprojectionsto

theamygdalaortothebednucleusofthestriaterminalis,which haveaccesstothebrainstemstartlecircuit[21].Primary acous-ticstartlepathwayinvolvesfewsynapsesincludingthecochlear rootneurons,neuronsinthenucleusreticularispontiscaudalis,and motoneuronsinthespinalcord[22].Sincethestartlereflexishigh sensitivetohabituation, sensitization,sensorimotor gating, and affectivemodulation,itmightbeusedtostudyseveralconditions includingfear and anxiety, affective disturbances, motivational states,andhomeostasis[13].Undoubtedly,Eag1K+_channel

block-adeeffectsinthestartleresponsemeritsfurtherinvestigation. Contrasting,consistentwithSwerdlowandco-workers[35]we shouldcarefullyinterpretingtreatmenteffectsinthePPIresponse inthe presenceof parallel effectson startleamplitude. Consis-tent withtheseauthorsit is possiblethat in thepresence of a reductioninthestartlemagnitudeinpulse-alonetrialsit is

dif-ficulttodeterminewhetherthelackof acomparable reduction

outrobustlyaffectingtheapomorphine-disruptiveeffectsinthe PPI.Weprovidethefirstdemonstrationofthepossibleinfluence ofthesechannelsinthestartleresponse,whichmayrepresenta biologicalimportantphenomenon.Althoughourresultsdonot sup-porttheclassicalantipsychotic-likeeffectstotheEag1K+_channels

blockadedatameritsfurtherstudies.

Acknowledgements

WewouldliketothankCéliaAp.daSilvaforthetechnical sup-port,andtoNadiaRubiaFerreira(PhD)whichfriendlygaveusthe

Eag1K+_channels_{immunohistochemistry}_{photomicrographs.}_This

researchwassupportedbyCNPqBrazilandCAPES/DAAD.

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