Plasticity of intrinsic neuronal excitability

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Dominique Debanne, Yanis Inglebert, Michaël Russier

To cite this version:

Dominique Debanne, Yanis Inglebert, Michaël Russier. Plasticity of intrinsic neuronal excitability.

Current Opinion in Neurobiology, Elsevier, 2019, 54, pp.73-82. �10.1016/j.conb.2018.09.001�.

�hal-01963474�

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Plasticity

of

intrinsic

neuronal

excitability

Dominique

Debanne,

Yanis

Inglebert

and

Michae¨l

Russier

Long-termsynapticmodificationisnottheexclusivemodeof memorystorage,andpersistentregulationofvoltage-gatedion channelsalsoparticipatesinmemoryformation.Intrinsic plasticityisexpressedinvirtuallyallneuronaltypesincluding principalcellsandinterneurons.Activationofsynaptic glutamatereceptorsinitiateslong-lastingchangesinneuronal excitabilityatpresynapticandpostsynapticside.Assynaptic plasticity,intrinsicplasticityisbi-directionalandexpressesa certainlevelofinput-specificityorcell-specificity.Wediscuss herethenatureofthelearningrulessharedbyintrinsicand synapticplasticityandtheimpactofintrinsicplasticityon temporalprocessing.

Address

UNIS,UMR1072INSERM–AMU,Marseille,France Correspondingauthor:Debanne,Dominique(dominique. debanne@inserm.fr)

CurrentOpinioninNeurobiology2019,54:73–82

ThisreviewcomesfromathemedissueonNeurobiologyoflearning andplasticity

EditedbyScottWaddellandJesperSjotrom

https://doi.org/10.1016/j.conb.2018.09.001 0959-4388/_ã2018ElsevierLtd.Allrightsreserved.

Introduction

Long-lastingplasticityofchemicalsynaptictransmissionis usuallyconsideredasthemainmechanismaccountingfor informationstorageinthebrain.Synapse-specificchanges intransmissionfromalargearrayofinputsappears particu-larlyappealingformaintainingahighcomputational capac-ityinthebrain.However,thisappearsnottobethewhole story and many otherfactors involved in thetransfer of neuronalinformationoccupytodayakeypositionin func-tional plasticity. Voltage-gated channels located at the inputoroutputsideofneuronsareinvolvedinaformof activity-dependentplasticitycalledintrinsicplasticity(for review,seeRefs.[1–5]).

Here,wereviewrecentinvitroworksdevotedtothestudy ofintrinsicplasticityinmammalianneurons.First,wewill discuss newexpressionmechanismsof gradedpersistent firing,aformofshort-termplasticitythatmayaccountfor workingmemory.Second,wereviewsomerecentfindings

thatillustratecellular correlatesoflearning mediatedby changes in intrinsic excitability. Next, we will describe differentwaysofmodulatinginput–outputfunctionatthe neuronalscale.Then,wewillconsiderthelearningrulesof intrinsicplasticityonthebasisofthosedefinedforsynaptic modifications. Next, we will review recently identified mechanismsofintrinsicplasticityinGABAergic interneur-ons.Finally,wewilldiscusstheconsequencesofintrinsic plasticityontemporalprocessing.

Graded

firing:

a

cellular

analog

of

working

memory

Workingmemory isanephemeral retentionof informa-tion whose neurobiological substrate can be seen as a stimulus-specific modulationof neuralactivitythatlasts untilanewstimulusispresented(Figure 1a).The neu-ronalbasisforthisformofmemorywasfirstidentifiedin associative cortices of themonkey (for review,see Ref. [6]).Intheprefrontalcortex,theposteriorparietalcortex or theinferotemporalcortex, asubsetof neurons called ‘memory neurons’ show persistent activity during a delayed response task, in which theanimal is required toretaininformationofasensorycueacrossadelayperiod between the stimulus and the behavioral response. In contrast with long-lasting forms of memory requiring molecular and/or structuralchanges, this form of short-term memory (or working memory) is a dynamic and ephemeral process. According to the classical view,the stimulationismemorizedthroughreverberatingactivity within interconnected groups of neurons (Figure 1b). Inhibitionofoneoftheneuronsmaystopactivitywithin interconnectedneurons.Egorovetal.[7]discoveredthat singleisolatedneuronsareabletomemorizethestimulus that was transiently applied (Figure 1b). During basal stimulation of muscarinic acetylcholine receptors (mAChR),neuronsfromtheentorhinalcortexmay,upon brief stimulation, generate sustained increases in their electricalactivitythataregradedinfrequencyand revers-iblebyhyperpolarization.Persistentfiringiscell-specific [8]andithasbeenalsoreportedinCA3[9]andCA1[10] hippocampal pyramidal neurons, mitral cells from the olfactory bulb [11] and L5 cortical pyramidal neurons [8,12]understimulationofmAChR.Gradedpersistent firing requires postsynaptic calcium influx mediated by spikingactivity.Theoriginalmechanismofgradedfiring was thoughtto be mediated by calcium-activated non-selective(CAN)cationiccurrentthatinturndepolarizes the cell [7] (Figure 1c). But, the molecular identity of CAN channels remains elusive and alternative mecha-nisms havebeen considered.The inversionof theNa+/ Ca2+exchangeractivitybyaccumulationof intracellular Na+hasbeenproposedtoaccountforpersistentfiringin

Availableonlineatwww.sciencedirect.com

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mitralcellsoftheolfactorybulb[11].Althoughattractive, this mechanism seems unable to explain all forms of persistent firingsince in neocortical pyramidal neurons, persistentfiringisstillobservedinthepresenceof tetro-dotoxin,apotentNavchannelblocker[12](inthiscase, calcium spikes replace sodium spikes). In this study, persistent firing is mediated by the modulation of ether-a`-Go-Go related gene (ERG) K+ channel [12]. ERGchannelsmediatealeakpotassiumcurrentthatis downregulatedbycalciumentryinducedwithrepetitive spiking(Figure 1c).

Cellular

correlates

of

learning

Thesearchforcellularexcitabilitycorrelatesoflearningand memory in the mammalian brain has focused on neurons that

are thought to be active during learning. Since the pioneering workofC.Woody,manystudieshaveshownthatclassical conditioningaltersintrinsicexcitability(IE)inneuronsfrom thepericruciatecortex[13], hippocampus[14,15]or cere-bellum[16].Allthesestudiesindicatethatintrinsicplasticity occursinneuronsfollowinglearningbuttheactivityofthe recordedcellwasnotaccuratelycontrolledduringlearning. A recent study went a step further by showing using a fluorescent activity-reporter that intrinsic excitability is alteredonlyincellsthatareactiveduringlearning[17].

Regulationsofneuronalexcitabilityhavebeeninvolved inothersformsof learning suchas spatiallearning[18], fear conditioning [19–22], odor discrimination [23–25]. Figure1

Na+ Ca2+

Nav channels Cav channels

CAN channel (a) (b) (c) Na+ ERG K channel stimulus

Reverberatory circuit Single neuron

Calcium influx

ADP Spike

Na+ Ca2+

Nav channels Cav channels

stim.

Current Opinion in Neurobiology

Persistentfiringasacellularmodelofworkingmemory.

(a)Briefexcitationoftheneuronbythestimulusleadstopersistentfiringthatispersistentlymaintainedatthesamerate.AdaptedfromRef.[7](b) Reverberatorycircuitversussingleneuronmnemonics.Inbothcases,anexternalstimulationleadstopersistentactivitythroughsynaptic connections(reverberatorycircuit)orthroughacalcium-dependentafterdepolarization(ADP).(c)TwopossiblemechanismsforADP.Left,the openingofCANchannelleadstosustainedfiringthroughNa+_influx_(adapted_from_Ref._[7])._Right,_the_closure_of_an_{ether-a`-gogo}_related_gene

(ERG)channelleadstopersistentfiringthroughadepolarizationofthemembraneconjugatedwithanincreaseininputresistance(adaptedfrom Ref.[12]).

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Experiencingneworenrichedenvironmentisalsoknown toaffectintrinsicexcitability[26,27].Followinglearning, usuallyafter-hyperpolarization(AHP),APthresholdand accommodation are decreased resulting in an enhance-ment of AP firingand neuronalIE in thehippocampus (spatialandfearconditioning),amygdala(fear condition-ing and odor discrimination), or prefrontal cortex (fear conditioning). While most of excitability changes dis-cussed so far corresponds to enhanced IE, decrease in IE has been observed in mitral cells of the accessory olfactory bulb following social learning [17]. In fact, mitral cells showed an unusual reduction in cell firing duringrepetitivestimulation.Thereasonwhypolarityis changesinthisparticularcaseisnotyetelucidatedbutit mayactto filtersustainedorrepetitive signals.

Multiple

mechanisms

for

modulating

input–

output

function

Input–output function is acritical operationachieved bysynapticandintrinsicmechanisms.Whereas expres-sionmechanismsofsynapticplasticityarerathersimple and involve either presynaptic change in neurotrans-mitter release or postsynaptic change in glutamate receptor density or function, plasticity of IE can be expressed through at least three different types of

functionalmodulation(Figure2).Ionchannelslocated indendritesshape EPSPwaveformbyeitherboosting or attenuating the synaptic response. Thus, a given EPSPmayleadtoanactionpotentialif thenet ampli-fication is enhanced. Two ion channels located inthe dendrites,thehyperpolarization-activatedcyclic nucle-otide-gated (HCN) channel and the voltage-gated potassiumchannel (Kv4.2) attenuatetheEPSP ampli-tude.Theirdownregulationfollowinginductionof syn-apticpotentiationenhancesinput–outputfunction[28– 31]. As synaptic plasticity, the modulation of EPSP amplification is generally local as other inputs remain unchanged[28,32].

Input–outputfunctionmaybealteredviamodulationof spikethreshold(Figure2).Thespikethresholdis deter-minedbyvoltage-gatedNa+(Nav)andK+(Kv)channels. Shift of Nav activation towards hyperpolarized values lowers the spike threshold and increases excitability followinginductionofsynapticpotentiationinCA1 pyra-midal neurons [33]. Similarly, downregulation of Kv1 channels, as observed in auditory neurons following cochlearemoval,lowersthespikethresholdandincreases intrinsic excitability [34]. This type of modulation is globalsince itmayaffectall incominginputs.

IntrinsicplasticityDebanne,InglebertandRussier 75

Figure2

EPSC

EPSP

EPSC EPSC

Receptors EPSP amplification

EPSC

LOCAL

GLOBAL

Spike threshold Resting potential

Synaptic

Intrinsic

(a) (b) (c) (d)

Mechanismsofinput–outputfunctionmodulation.

(a)Synapticmodificationofinput–outputfunction.Localpotentiationofsynaptictransmissionbyincreaseintransmitterreleaseand/or

postsynapticreceptordensityischaracterizedbyanenhancedexcitatorypost-synapticcurrent(EPSC).Attheinitialsegment,theexcitatory post-synapticpotential(EPSP)becomeslargeenoughtocrosstheactionpotential(AP)thresholdandtoelicitapostsynapticspike.Notethelarger EPSPslope.(b)ChangeinEPSPamplification.Whendendriticchannels(red)areregulated,theresultingEPSPisamplifiedandcrossesthespike threshold.Notethatherethesynapticcurrent(EPSC)iskeptconstanttoclearlydistinguishintrinsicfromsynapticchangesandtheinitialEPSP sloperemainsunchanged.Thesefirsttwomodificationsarelocalbecausetheydonotaffectallsynapticinputs.(c)Changeinspikethreshold.An increaseinspikefiringisobtainedwhentheAPthresholdishyperpolarizedthroughtheregulationofvoltage-gatedionchannelslocatedatthe axoninitialsegment.Hereagain,synapticcurrent(EPSC)remainsunchanged.(d)Changeinrestingmembranepotential.Followingmodulationof voltage-gatedchannels,therestingmembranepotentialoftheneuronisdepolarizedleadingtothetriggeringofanactionpotentialbytheEPSP. Notethathereagain,synapticcurrent(EPSC)remainsunchanged.Theselasttwomodificationsareglobalbecausetheyaffectallsynapticinputs.

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Input–outputfunctioncanbemodulatedbychangingthe resting membranepotential(RMP) of theneuron( Fig-ure 2). Hippocampal granule cells display long-term depolarization(LT-Depol)oftheRMPbyapproximately 8–10mVfollowinghighfrequencyfiring[35].LT-Depol ingranulecellsismediatedbyaproteinkinase A-depen-dentupregulationofHCNchannels. While,the regula-tionofHCNchannelsleadsto attenuatedEPSP ampli-tudeandthereforetoareductioninintrinsicexcitability (seeabove),theneteffecthereishoweveranincreasein excitability. In fact, the large depolarization of resting membrane potential (8–10mV) largely dominates the excitabilityreductioncausedbytheattenuationof excit-atorysynapticinputs.Thissustaineddepolarizationmay notonlyleadtogranulecellfiringinresponsetoincoming excitatory inputs but also to the facilitation of

transmission at their mossy-fiber boutons through an analog-digitalsignalingmechanism[36].Hereagain,this modulationisglobalasallinputswillbeequallyaffected.

Learning

rules

of

intrinsic

plasticity

HebbianchangesinIE

Hebbian plasticity has been first defined for synaptic transmission in the form of the Bienenstock-Cooper-Munro (BCM) rule. BCM rule stipulates that synaptic modificationcorrelateswiththeactivitymodulation dur-inglearning(forarecentreview,seeRef.[37];Figure3a). Hebbiansynapticmodification in thehippocampusand neocortex is also induced by the degree of correlation between presynaptic and postsynaptic activity and is referredtoasspike-timingdependentplasticityorSTDP [38].BothtypesofHebbianplasticityareassociatedwith

Figure3 Synaptic Intrinsic LTD LTP LTD LTP

Hebbian plasticity rules

Stimulation frequency Spike timing

Synaptic change Intri n si c chang e Synergy BCM STDP 0

Homeostatic plasticity rule

Activity

Intrinsic

Hebbian-Homeostatic plasticity rule

Activity Intrinsic (a) (b) (c) EPSP-Spik e coupling EPSP-Spik e coupling EPSP sum m a ti on Presy n . ex citability θD θP EPSP slope

Cooperationbetweensynapticandintrinsicplasticityrules.

(a)Synergisticchangesinsynapticandintrinsicplasticity(Hebbian).Left,BCM(Bienenstock-Cooper-Munro)ruledefinessynergisticsynapticand intrinsicmodificationfollowinglow(uD<frequency<uP)orhigh(>uP)stimulationfrequency.uD=LTDthreshold,uP=LTPthreshold.Adapted

fromRef.[41].Middle,STDP(spike-timingdependentplasticity)ruledefinessynergisticsynapticandintrinsicmodificationfollowingnegativeor positivespiketiming.AdaptedfromRefs.[28,32,50,51].Right,synapticandintrinsicplasticitychangesynergistically.AdaptedfromRefs.[32,41]. (b)Homeostaticplasticityrule.Increaseinsynapticactivityinducesanoppositedecreaseinexcitabilitywhereasreductioninsynapticdrive inducesanelevationinexcitability.Notethathomeostaticplasticityruleonlyaccountsforintrinsicexcitabilitychangesfollowingloworhigh,but notforintermediatechangesinsynapticactivity.AdaptedfromRefs.[56,63,64].(c)Hebbian-homeostaticplasticityrule.Thisplasticityrulelinks homeostaticplasticityasdefinedinpanel(b)toHebbianchangesinintrinsicexcitabilityasdefinedinpanel(a).AdaptedfromRefs.[29,69].

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intrinsic plasticity that are synergistic to the induced synaptic changes(Figure 3a).

Atthepostsynapticside,synapticmodificationsare asso-ciated with synergistic plasticity of IE that affects the input–outputfunctionoftheneuron(i.e.excitatory post-synapticpotential-spike(orEPSP-spike)coupling;seefor review Refs. [1,39]). In CA1 pyramidal neurons, long-term synaptic potentiation (LTP) is associated with an increasedfiringprobabilityinresponsetothetetanizedor paired input [32,40,41] whereas long-term synaptic depression (LTD) is associated with adecreased firing probability in responseto thestimulated input [32,41]. EPSPsummationischangedsynergisticallywithsynaptic modifications induced by STDP protocols [28] (Figure3a).AlltheseHebbianmodificationsinIErequire NMDA-receptoractivationandareinput-specific,thatis nomodificationoccursonotherinputs.Hebbianintrinsic plasticityisnotspecifictohippocampalneuronsand long-lasting increase in IE has been induced in neocortical neurons following synaptic [42] or intrinsic [43,44,45] activationparadigms.

Intrinsic plasticity has been reported in at least three differenttypesofcerebellarneurons.Indeepcerebellar nuclei, granule and Purkinje neurons, IE is enhanced following highfrequency stimulationthatinducesLTP [46–48]. Here again, NMDA-receptor activation is requiredfor inductionofintrinsicplasticity.InPurkinje cells,enhancedIEismediatedbythedownregulationof SK channelsand requires activationof PKA and casein kinase 2(CK2).As in corticalneurons,the reciprocalis trueandlong-lastingdecreaseinIEisobservedfollowing LTD induction[49].ThisLTD-IE is mediatedbythe upregulationofHCNchannels.

SynergisticchangesinIEhavebeenalsoidentifiedatthe presynapticsidewhenLTPorLTDisinducedbySTDP protocolsinhippocampalandneocorticalneurons[50,51] (Figure3a).IEinthepresynapticneuronwasfoundtobe enhanced followinginductionof synapticLTPby posi-tive correlation whereas IE of the presynaptic cell was decreased followinginductionofLTDbynegative cor-relation. Presynaptic intrinsic plasticity involves yet unidentifiedretrogrademessengersandmightbeofgreat importanceforthedynamicsofneuralcircuitsbycreating privileged pathways of activity in the brain where pre-synapticandpostsynapticexcitabilityaswellassynaptic transmissionchangeharmoniously.

HomeostaticplasticityofIE

Hebbianmechanismsappearinsufficienttoexplain activ-ity-dependent plasticity during development because theytendtoreinforceactivecircuitsanddepressinactive onesandarethusdestabilizing.Infact,stabilityinneural circuits can be achieved by introducing homeostatic plasticity that adjust synaptic strength and intrinsic

excitability [52]. Initially reported in cultured visual cortical neurons [53], homeostatic plasticity of IE has been observed in virtually all neuronal types. IE is enhanced in response to chronic activity deprivation induced pharmacologically [54–57]or by sensory depri-vation [34,58,59],whereas itisreduced in responseto elevatednetworkactivity[54,56,60],leadingtoa homeo-static plasticity rule that is globally anti-Hebbian (Figure 3b).

While many ionchannelsare regulated in parallel[61], two inhibitory channels have recently retain attention: Kv1 channelslocated in theaxon thatdetermine spike thresholdandintrinsicexcitability[62],andHCN chan-nelslocatedinthedendritesthatdampensall depolariz-ingeventssuchasEPSPs.DownregulationofKv1 chan-nelactivityhasbeenidentifiedasamajormechanismfor the increased excitability observed in CA3 pyramidal neurons after chronic blockade of glutamate receptors [55]andin auditoryneuronsfollowingcochlear removal [34].Conversely,Kv1currentsareupregulated follow-ingepileptiformactivity[60],indicatingthatKv1channel activity is bi-directionally regulated. In CA1 pyramidal neurons, HCN channels are homeostatically regulated following bidirectionalchronicmanipulationofnetwork activity [56] or following induction of large synaptic modification[63,64].

Whereashomeostaticplasticityincorticalpyramidalcells is usually induced by persistent modulation of activity lastingfew tensof hours[53–56],homeostatic potentia-tionofIEcanbeinducedbyatransienthyperpolarization (20–300s)investibularneurons[65]andcerebellarGolgi cells [66]. Both forms of plasticity involve the down-regulation of BK channel activity. It should be noted thatin contrastto pyramidalcellsthat aresilentatrest, thesecellscorrespondtopacemakerneuronsthat contin-uously fire at5–10Hz. Interestingly, vestibular sensory losstriggersrapidpotentiationofexcitabilityinvestibular neurons thus enabling adaptive compensatoryincreases in optokineticreflexgain[67].

LinkingHebbianandhomeostaticintrinsicplasticity

Despitetheirapparentantagonisticfeature,Hebbianand homeostaticplasticityarethoughttoworkhand-in-hand [68].Themodulationof HCNchannelfollowing induc-tionofsynapticmodificationprovidesagoodexamplefor such interaction. Whereaslarge LTPis associatedwith decreased IE due to theupregulationof HCN channel activity[63],small LTPiscombinedwith increasedIE resultingfromdownregulationofHCNchannel[32].The oppositeistrueforLTDwithaHCN-dependentincrease inIEinducedinparalleloflargeLTD[64]anda HCN-dependent decrease in IE for small LTD [69]. The multiple regulation of HCN channel implies distinct inductionandexpressionpathways[63,64,69,70].Thus, IntrinsicplasticityDebanne,InglebertandRussier 77

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IE follows a single plasticityrule linking Hebbian and homeostaticplasticity(Figure3c).

Intrinsic

plasticity

in

GABAergic

interneurons

Intrinsicplasticityisnotexclusivelyexpressedinprincipal neuronsandGABAergicinterneuronsalsodisplayseveral formsoflong-termintrinsicplasticity.Basketcellsofthe dentategyrusexhibitLT-Depoloftheirrestingmembrane potentialfollowinghigh-frequencystimulationofthe glu-tamatergic inputs [71]. As in granule cells, LT-Depol

enhances the efficacy of EPSPs to fire the interneuron butinbasketcellsLT-Depolresultsfromchangesinthe Na+/K+ATPasepumpfunctionandrequirestheactivation ofcalcium-permeableAMPAreceptor.

Voltage-dependent excitability is also finely tuned in basketcells byKv1-dependentmodulation ofthespike threshold to adjust inhibition levels in cortical circuits. StimulationoftheNeuregulin1receptorErbB4hasbeen shown to strongly regulate Kv1 channel activity and Figure4

Stimulated

Unstimulated

Highly

excitable

PV BC

Weakly

excitable

PV BC

inhibition no inhibition Kv1 Er81 (a) Kv1 Er81 (b) 20 mV 0 10 20 30 40 0 5 10 15 20 25 30 35 40 45

Frequency

(Hz)

Count

Sp

Cls

46%

100 ms

Before

0 10 20 30 40 0 5 10 15 20 25 30 35 40 45

Frequency

(Hz)

Count

84%

After LTP-IE

IntrinsicplasticityinGABAergicinterneurons.

(a)Bidirectionalregulationofintrinsicexcitabilityinparvalbuminpositivebasketcells(PV-BC).Left,inunstimulatedconditions,noinhibitionis observedbecausethePV-BCisnotrecruitedbythecircuitastheconsequenceofelevatedlevelsofKv1channelsintheaxonthrough activity-dependentelevationofthetranscriptionfactorEr81.Right,instimulatedconditions,PV-BCisrecruitedbecauseofreducedlevelsKv1channels throughactivity-dependentreductioninEr81,leadingtofunctionalinhibitionthatcounterbalanceenhancedexcitation.AdaptedfromRefs. [73,74,75].

(b)ModulationoftemporalprocessinginPV-BC.Incontrolconditions,PV-BCdisplayaspecificmodeoffiringcomposedofsparsespikes(Sp) typicallyoccurringafteraslowdepolarizingrampofpotentialataninstantaneousfrequencyof10Hz(i.e.thetafrequency)andclusteredspikes (Cls)thatimmediatelyfollowaspikeataninstantaneousfrequencyof30Hz(i.e.gammafrequency).Afterinductionoflong-termpotentiationof intrinsicexcitability(LTP-IE),theproportionofClsincreasesfrom46to84%indicatingagainofspikingactivityinthegammafrequencyrange. AdaptedfromRef.[73].

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intrinsicexcitabilityinparvalbuminpositivebasketcells (PV-BC)[72].Likewise,PV-BCsexhibitpotentiationof IE mediated by the downregulation of Kv1 channel activity and induced by synaptic activation of metabo-tropic glutamate receptor subtype 5 (mGluR5) [73] (Figure 4a). This facilitation is responsible for most of the increased firing and is thought to compensate enhanced synaptic and intrinsicexcitation in pyramidal neurons. The reciprocal modulation has been recently observed in somatosensory PV interneuron following activity-deprivation[74],indicatingthatKv1-dependent regulation of neuronal excitability is bidirectional (Figure4a).Inthecortex,mostPVinterneuronsexpress Er81, a transcription factor involved in the activation pathway of Ca2+/calmodulin-dependent kinase I [75]. Noteworthy, Er81 is highly regulated by activity and controls levels of Kv1.1 channel in PV interneurons [75].Infact,Er81levelishighinweaklyactivecircuits whereas itislowin highlyactivecircuits(Figure 4a).

Incidence

of

intrinsic

plasticity

on

temporal

processing

Temporalprocessingisthoughttorepresentakeyfactor inbrainfunctionandiscontrolledbysynapticcircuitsand byintrinsicproperties[76,77].Forexample,duringinitial storageof fearlearning,spikingactivityamongadjacent CA1pyramidalneuronsbecomesmoresynchronized[78]. At a cellular scale, spike-timing, membrane resonance andpacemakeractivityareallcontrolledbyvoltage-gated ionchannelsincludingthoseinvolvedinintrinsic plastic-ity[55,79,80].BothHebbianandhomeostaticregulations of IEareassociatedwithimprovedspike-timeprecision [42,45,55].Inallcases,improvedprecision resultsfrom an ion channel-dependent enhancement of the voltage rising-slope precedingtheaction potential.

HCNchannelssetresonancefrequencyinhippocampal CA1 neurons in the u range. Following large synaptic modifications, theresonance frequencyis modulatedas the sign of the induced synaptic change through mod-ificationsinHCNchannelproperties[64,81].Thisshows thatoscillatoryintrinsicdynamicsinthehippocampuscan befinelytunedunderhomeostatic plasticityof IE. Modulation ofthetemporalstructure of firinghasbeen describedintwocelltypes.InPurkinjecells, SK-depen-dent enhancement of intrinsic excitability leads to increased burst firing in response to climbing fiber dis-chargeandshorteningofspikepauses[82].AsPurkinje cells inhibit deep cerebellar nuclei, these briefer spike pausesareseenasenhancedexcitationattheoutputside of the cerebellum. Likewise, enhanced IE in PV-BC promotes clustered spiking activity in the gamma-fre-quency range [73] (Figure 4b). As PV-BC represents the maincell-type orchestrating network oscillations in the hippocampus, this modulation in the temporal

structureofPV-BCfiringsuggestsuse-dependent modu-lationof gammaoscillations[83].

Conclusion

and

perspective

Remarkableprogressinunderstandinglearningrulesand inidentifyingmechanismsofintrinsicplasticityhasbeen madetheserecentyears.However,manyissuesremain. Forinstance,moststudiesreportedinthisreviewcomes from in vitro works and very few studies have been performed invivo [44,45] with physiologically realistic inductionprotocols.Onemaydreaminthenearestfuture ofmonitoringIEincorticalorcerebellarneuronsduring the acquisition of asimple behavioraltask. To achieve this goal, development of new tools will be required. Another challengewillconsist inidentifyingwhy oppo-sitechangesinintrinsicexcitabilityisobservedin differ-enttypesofneuronwithinthesamestructure following sensory deprivation [58,84].Whereas changesin IE are clearly homeostatic in layer 2/3 principal neurons [58], theyareHebbianinlayerfive pyramidalcells[84].The futurewill probablyhelpto answerallthesequestions.

Conflict

of

interest

statement

Nothingdeclared.

Acknowledgements

SupportedbyINSERM,CNRS,AMU,FRM(FDT2170437059& DVS20131228768)andANRNEUC2014(ANR-14-NEUC-0004).

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