hyperpolarization-activated cyclic nucleotide-gated (hcn)...

Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Channels in Epilepsy

Gary P. Brennan1, Tallie Z. Baram1,2, and Nicholas P. Poolos3

1Department of Pediatrics, University of California-Irvine, Irvine, California 92697-44752Departments of Anatomy/Neurobiology and Neurology, University of California-Irvine, Irvine, California92697-4475

3Department of Neurologyand Regional Epilepsy Center, University of Washington, Seattle, Washington 98104

Correspondence: [email protected]

Epilepsy is a common brain disorder characterized by the occurrence of spontaneous sei-zures. These bursts of synchronous firing arise from abnormalities of neuronal networks.Excitability of individual neurons and neuronal networks is largely governed by ion channelsand, indeed, abnormalities of a number of ion channels resulting from mutations or aberrantexpression and trafficking underlie several types of epilepsy. Here, we focus on the hyper-polarization-activated cyclic nucleotide-gated ion (HCN) channels that conduct Ih current.This conductance plays complex and diverse roles in the regulation of neuronal and networkexcitability. We describe the normal function of HCN channels and discuss how aberrantexpression, assembly, trafficking, and posttranslational modifications contribute to experi-mental and human epilepsy.

HCN CHANNELS AND Ih IN THE BRAIN

Expression, Assembly, and SubcellularDistribution

Hyperpolarization-activated cyclic nucleo-tide-gated ion (HCN) channels conduct

the Ih current and are encoded by four genes(HCN1, HCN2, HCN3, and HCN4) (Santoroet al. 1997, 1998; Gauss et al. 1998; Ludwig etal. 1998; Ishii et al. 1999). Structurally similar tovoltage-gated Kþ channels, HCN channels areformed as a tetramer of subunits, each with asix-transmembrane domain topology, includ-ing a pore region that conducts ion flow, andintracellular amino and carboxyl termini. FourHCN molecules of the same isotype can assem-

ble as homomeric channels. However, the fourisoforms can also functionally assemble in dif-ferent combinations to form heteromeric chan-nels with different properties (Robinson andSiegelbaum 2003; Santoro and Baram 2003;Brewster et al. 2005; Biel et al. 2009; Zolles etal. 2009). The variation in Ih properties amongcell types and developmental stages is likely aresult of differential expression of variousHCN isoforms in both homomeric and hetero-meric forms (Kuisle et al. 2006; Brewster et al.2007; Bender and Baram 2008; Kanyshkovaet al. 2009). For example, the isoform predom-inantly expressed in cortex and hippocampus,HCN1, endows the current with more rapidactivation kinetics and a minimal sensitivity

Editors: Gregory L. Holmes and Jeffrey L. Noebels

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to cyclic adenosine 30, 50-monophosphate(cAMP), whereas Ih in cells from thalamusand cardiac sinoatrial node where the primaryisoform expressed is HCN2 or HCN4 showsslower activation and substantial sensitivity tocAMP (Biel et al. 2009; Noam et al. 2011). Inaddition, the profile of HCN subunit expressionin a specific neuron may vary during develop-ment (Brewster et al. 2007).

Interactions with associated proteins greatlyinfluence the function of HCN channels, alsoin an isoform-specific manner (Santoro et al.2004; Lewis et al. 2009; Zolles et al. 2009; Lewisand Chetkovich 2011; Noam et al. 2014). Theconductive properties of HCN channels arefurther regulated by interactions with moleculessuch as cAMP. cAMP binds a sequence on thecarboxyl terminus of the channel and influencesHCN function by accelerating its kinetics andshifting its voltage-activation curve to moredepolarized values (Robinson and Siegelbaum2003; Biel et al. 2009). The sensitivity of HCNchannels to cAMP is isoform specific withHCN4 . HCN2 .. HCN1. The number ofHCN channels expressed on a cell’s surface in-fluences the magnitude and properties of Ih (seebelow). HCN expression is regulated by neuro-nal and network activity in an isoform-depen-dent manner (Brewster et al. 2002; Noam et al.2011). Other factors that influence HCN mem-brane expression are posttranscriptional modi-fications, particularly glycosylation and phos-phorylation (Jung et al. 2010; Williams et al.2015). HCN channels undergo extensive glyco-sylation and the extent of glycosylation influ-ences the number of channels expressed on themembrane (Much et al. 2003; Zha et al. 2008)and their homomeric or heteromeric assembly(Zha et al. 2008; Hegle et al. 2010).

The function of HCN channels depends alsoon their subcellular distribution (Magee 1998;Poolos et al. 2002; Berger et al. 2003; Santoroand Baram 2003; Aponte et al. 2006; Benderet al. 2007; Ying et al. 2007; Noam et al. 2010;Wilkars et al. 2012). Subcellular localizationcan vary dramatically among different neuronalsubtypes and includes somatic, dendritic, andaxonal. In cortical and hippocampal pyramidalcells, for example, HCN channels localize pri-

marily to dendrites where they regulate theintegration and summation of synaptic input(Stuart and Spruston 1998; Magee 1999; Lo-rincz et al. 2002; Poolos et al. 2002; Bergeret al. 2003; Wang et al. 2003; Brewster et al.2007). Furthermore, in cortical and hippocam-pal interneuronal populations, HCN channelslocalize preferentially to the somatic region ofthe cell where they coregulate cellular propertieslike the resting membrane potential and sponta-neous firing frequency (Maccaferri and McBain1996; Lupica et al. 2001). Axonal HCN channelshave been identified in a subgroup of interneu-ron populations as well as in certain excitatoryneurons (Notomi and Shigemoto 2004; Lujanet al. 2005; Aponte et al. 2006; Brewster et al.2007). HCN channels are also found in axonalterminals of a subset of entorhinal neuronswhere they act to inhibit presynaptic glutamaterelease (Bender et al. 2007; Huang et al. 2011).

The subunit composition, channel phos-phorylation, and interaction with accessoryproteins and other ion channels contribute sig-nificantly to the different biophysical propertiesof HCN channels on diverse neuronal popula-tions in different brain regions (Chen et al.2002; George et al. 2009; Jung et al. 2010; Ham-melmann et al. 2011). In addition, the contri-bution of HCN channels to neuronal excitabil-ity depends on their subcellular localization,the type and levels of coexpressed ion channels,the nature and strength of synaptic inputs, andlikely other as-yet less-well-defined properties(Noam et al. 2011). In fact, as was first describedin 1998, HCN channels in pyramidal neuronsare arrayed in a gradient density pattern alongthe somatodendritic axis, reaching a density inthe distal dendrites that is seven- to 10-fold thatof the soma (Magee 1998; Lorincz et al. 2002).This nonuniform somatodendritic distribu-tion of ion channel subunits turns out to be aproperty of a number of other voltage-gatedion channels as well, including the Kþ chan-nel Kv4.2 and the Ca2þ channel Cav2.3 (Beckand Yaari 2008; Nusser 2009). The dendri-tic predominance of HCN channel distributionin pyramidal neurons appears to be mediated inpart by interaction with an accessory pro-tein, TPR-containing Rab8b-interacting protein

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(TRIP8b). This protein binds to the carboxylterminus of the HCN protein and increasesits surface membrane expression in pyramidaldendrites(Lewisetal.2009;Santoroetal.2009;Le-wis and Chetkovich 2011). Interestingly, HCNchannel trafficking to the axons of entorhinal cor-tical neurons is independent of TRIP8b (Huanget al. 2012). Conversely, filamin A binding withHCN channel subunits decreases their surfacemembrane expression via dynamin-dependentendocytosis (Noam et al. 2014). Thus, accessoryprotein interactions underlie HCN channel traf-ficking,andmaycontributetoactivity-dependentregulation of their expression.

PROPERTIES OF Ih AND ITS ROLE INREGULATION OF NEURONAL ANDNETWORK EXCITABILITY

HCN channels generate Ih, a current with un-usual biophysical properties (Accili et al. 2002;Robinson and Siegelbaum 2003; Biel et al.2009). As mentioned above, they are structural-ly similar to Kþ channels but lack their highselectivity for Kþ ions and, in fact, conductmostly Naþ ions under physiological condi-tions. Thus, Ih is an inward, depolarizing cur-rent. The voltage-dependent activation of HCNchannels is also atypical, increasing with hyper-polarization from rest rather than with de-polarization as is common with other channels.Thus, neuronal depolarization tends to inacti-vate HCN channels, whereas hyperpolarizationtends to activate them. HCN channels do notdisplay inactivation, being fractionally openand active around resting potential. Indeed,the channels contribute to the resting potential,such that neurons expressing HCN channelstypically have a more depolarized resting mem-brane potential than those that do not expressthe channel (Lupica et al. 2001; Mesirca et al.2014). This biophysical feature of Ih constitutesa critical contribution to the regulation of neu-ronal excitability. Because HCN channels areone of the few voltage-gated channels open atresting potential, Ih comprises about half of theresting conductance of many neuron types. Thisallows HCN channels to exert a strong influenceon neuronal resting potential and input resis-

tance. Finally, HCN channel activation is mod-ulated by cyclic nucleotides such as cAMP.Numerous signaling pathways that alter intra-cellular cAMP levels, therefore, modulate HCNchannel activity.

Ih produces an inward current yet is deacti-vated (with a slow time course on the order oftens of msec) by depolarization; this yields aninherent negative-feedback property that im-parts a stabilizing effect on neuronal excitabili-ty. For example, neuronal depolarization deac-tivates the steady-state inward current producedby HCN channels, hyperpolarizing the mem-brane potential back toward rest. Conversely, ahyperpolarizing input will turn on Ih, depolar-izing the neuron back toward rest, an action thatmight also lead to rebound depolarization andaction potential firing (Chen et al. 2001). Pairedwith an inactivating inward conductance, suchas a transient “T-type” Ca2þ current, Ih contrib-utes to rhythmic “pacemaker” activity, such as isseen in thalamocortical neurons, cardiac sino-atrial nodal cells, and neurons in the basal gan-glia (McCormick and Bal 1997; Huguenard2001; Chan et al. 2004).

The pacemaking function of HCN channelsis prominent when they are localized in the cellsoma near the sites of action potential genera-tion. In neocortical and hippocampal pyrami-dal neurons, HCN channels are localized atlow density in the soma and at higher densityin the apical dendrites. This dendritic localiza-tion produces an additional inhibitory effect.Within the dendrites, resting Ih conductanceconstitutes a “leak” that diminishes the inputresistance of the dendrites to incoming synapticcurrents, decreasing the voltage change pro-duced by an excitatory postsynaptic potential(EPSP) and decreasing the ability of synapticinput to drive action potential firing. Converse-ly, when Ih is inactivated, input resistance ishigher and EPSPs are increased in magnitude.The effect of Ih on dendritic input resistance isaugmented by an interaction with M-type Kþ

channels present in the dendrites (George et al.2009). Thus, Ih causes both resting potentialdepolarization that promotes hyperexcitabilityand an inhibitory effect on action potentialfiring. Several important studies found that

HCN Channels in Epilepsy

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pharmacological inhibition of Ih or genetic de-letion of HCN1 channels increases excitabilityin neocortical and hippocampal pyramidalneurons. For example, increased summationof excitatory synaptic inputs in hippocampaland neocortical pyramidal neurons was foundon pharmacological inhibition of Ih (Bergeret al. 2001; Poolos et al. 2002). Genetic deletionof HCN1 channels or pharmacological block-ade in vivo of HCN channels enhanced synapticplasticity and spatial learning (Nolan et al. 2004;Wang et al. 2007) and increased dendritic Ca2þ

spiking (Tsay et al. 2007). However, in neurons,including interneurons, where Ih does not havea prominent dendritic localization, its depolar-izing action on resting potential yields a pre-dominantly excitatory influence, for example,on the spontaneous activity of interneurons(Lupica et al. 2001).

HCN CHANNELS IN EPILEPSY: ANIMALSTUDIES

HCN Expression and Function in ExperimentalEpilepsy Studies

Rodent models of seizures and epileptogenesishave provided direct evidence for activity-dependent effects on HCN channel expressionand function. The first studies to implicateHCN channel expression changes in epilepto-genesis involved the hyperthermia-inducedseizures in infant (p10) rats. These seizures re-sulted in chronic enhancement of Ih in CA1pyramidal neurons and were associated with amodest depolarizing shift of the voltage depen-dence of Ih, and significant slowing in the ac-tivation and deactivation kinetics (Chen et al.2001). These changes persisted for weeks tomonths following the initial epilepsy-inducinginsult. Follow-up studies examined the molec-ular basis of the changes in HCN function andsuggested that altered channel properties result-ed from a change in the relative abundance ofHCN1 and HCN2 channels in favor of theslower HCN2. Specifically, studies of the expres-sion pattern of HCN channels following devel-opmental prolonged febrile seizures and alsokainate-induced seizures found persistent loss

of HCN1 messenger RNA (mRNA) and proteinexpression, transient down-regulation of HCN2expression (Brewster et al. 2002, 2005), andincreased formation of heteromeric HCN1/HCN2 channels (Brewster et al. 2005).

Subsequent to the initial description of re-duced HCN1 expression and increased Ih avail-ability in the experimental febrile status epi-lepticus (SE) model, this loss of HCN1channel expression coupled with reduction ofIh has been the most common finding in rodentmodels of acquired epilepsy (Table 1). Thechanges in Ih biophysical parameters, HCN1channel protein expression, and HCN1 tran-scription suggest that multiple mechanisms un-derlie the acute and chronic loss of HCN1 chan-nel expression and function following anepileptogenic brain insult. In post-SE models,Ih in the dendrites of pyramidal neurons is re-duced as rapidly as 1 h post-SE, and remains soat least for a month, at a point when the animalis chronically epileptic (Shah et al. 2004; Mar-celin et al. 2009; Jung et al. 2011). Some model-dependent differences in the time course of thisprocess have been observed, that may be a func-tion of the severity of the resulting epilepsy phe-notype, with the pilocarpine model tending toproduce a more rapidly developing epilepsythan kainate or experimental febrile SE (Dubeet al. 2006; Jung et al. 2007; Williams et al.

Table 1. Listing of studies in various epilepsy modelsthat detect decreased HCN1 expression within theCA1 region of the hippocampus

Study Model

Hippocampal

region

(Brewster et al. 2002) Febrile seizures CA1(Shah et al. 2004) Systemic KA EC layer III(Jung et al. 2007) Pilocarpine CA1(Powell et al. 2008) Systemic KA/

kindlingCA1, CA3,

DG, EC(Marcelin et al. 2009) Pilocarpine CA1(Jung et al. 2010) Pilocarpine CA1(Jung et al. 2011) Pilocarpine CA1(McClelland et al.

2011)Systemic KA CA1

HCN, Hyperpolarization-activated cyclic nucleotide-

gated ion; KA, kainic acid; DG, dentate gyrus; EC,

entorhinal cortex.

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2009). In addition, loss of HCN channel expres-sion has been observed following other braininsults, including perinatal hypoxia (Zhanget al. 2006), cortical dysplasia (Hablitz andYang 2010; Li et al. 2012), and subarachnoidhemorrhage. Indeed, a common regulatorymechanism consisting of an increase in the ex-pression of the repressor neuron-restrictive si-lencer factor (NRSF/repressor element-1 silenc-ing transcription factor [REST]), that potentlyrepresses HCN1 and other key neuronal genes,might exist in these scenarios (McClelland et al.2011, 2014).

Several mechanisms underlying loss of Ih

following a brain insult have been elucidated.In pyramidal neuronal dendrites, loss of Ih am-plitude within the first hour post-SE is accom-panied by a loss of surface membrane expressionof HCN1 channel subunits, whereas total chan-nel protein expression is unchanged suggestingthat HCN1 channel subunits are rapidly inter-nalized following SE (Jung et al. 2011). In severalmodels, reduction in HCN1 mRNA expressioncan be detected starting at 8, 16, or 48, to 72 hfollowing the insult. This is mediated by in-creased expression and activity of NRSF. NRSFbinds to a cognate binding site (neuron-restric-tive silencer element [NRSE]) situated withinthe first intron of the HCN1 gene (McClellandet al. 2011). Indeed, when the function of NRSFwas inhibited following kainic acid (KA)-in-duced seizures by using NRSE-containing oli-godeoxynucleotides, the expression of HCN1was rescued and Ih was restored (McClellandet al. 2011). Importantly, inhibition of NRSFfunction following KA-induced seizures signif-icantly ameliorated the subsequent epilepticphenotype. Although restitution of HCN1 ex-pression and Ih is unlikely to be responsible forthis amelioration (because NRSF regulates thetranscription of numerous genes) (McClellandet al. 2014), it implicates HCN channel dysregu-lation and dysfunction as a contributing factorto the epileptogenic process.

Another factor contributing to the loss of Ih

in epilepsy is a down-regulation of voltage-de-pendent activation or “gating.” Although Ih am-plitude and HCN1 channel expression are re-duced by �50% following SE, the remaining

channels also show a hyperpolarizing shift intheir gating, reducing the fraction of channelsthat are activated at typical neuronal resting po-tential, thus promoting hyperexcitability (Chenet al. 2001; Jung et al. 2007). HCN channelgating is strongly modulated by phosphoryla-tion-dependent mechanisms, with down-regu-lation correlating with decreased phosphoryla-tion mediated by either the protein kinase p38mitogen-activated protein kinase (MAPK) orincreased activity of the protein phosphatase2B (PP2B or calcineurin). Hippocampal tissuefrom chronically epileptic animals shows a lossof p38 MAPK activity with a concomitant in-crease in PP2B activity; pharmacological rever-sal of these phosphorylation signaling changesleads to normalized HCN channel gating andreduced neuronal hyperexcitability (Jung etal. 2010). This suggests that posttranslationalsignaling mechanisms, in addition to transcrip-tional mechanisms, contribute to HCN chan-nelopathy in epilepsy models.

Other lines of evidence indicating a role forHCN channels in neuronal excitability and ep-ilepsy have come from studies demonstratingthe effects of clinically used antiepileptic drugson Ih. The first such demonstration showed thatacetazolamide up-regulated Ih via a depolariz-ing shift in gating of Ih recorded from thalamicneurons (Munsch and Pape 1999). Subse-quently, lamotrigine was found to up-regulateIh in hippocampal pyramidal neurons, also byan action on gating (Poolos et al. 2002), whereasgabapentin increased the maximal currentamplitude (Surges et al. 2003). Interestingly,up-regulation of Ih by lamotrigine increasedthe spontaneous action potential output of hip-pocampal interneurons, enhancing the inhibi-tion of pyramidal neurons (Peng et al. 2010).

Knockout and Genetic Model Studies

The advent of genome manipulation in micehas significantly aided our understanding ofthe role of HCN channels in pathological con-ditions such as epilepsy. Deletion of the HCN2gene revealed that HCN22/ – mice had gen-eralized, spike-wave electroencephalographic(EEG) discharges, consistent with generalized



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epilepsy. Whole-cell current-clamp recordingsfrom thalamocortical neurons from HCN22/ –

mice revealed stereotyped high-frequency burstdischarges, suggesting that HCN2 channel ex-pression is required for normal thalamocorticaloscillations, and its absence promotes epilepsy(Ludwig et al. 2003). These findings show thatloss of HCN2 channel function, most likely inthalamic nuclei, are sufficient to produce anepilepsy phenotype.

Analysis of HCN channels in thalamocor-tical neurons in inbred rat strains with general-ized epilepsy, such as Genetic Absence EpilepsyRats from Strasbourg (GAERS), and Wistar Al-bino Glaxo/Rij (WAG/Rij) rats show abnormalHCN channel expression (Fig 1). In the GAERSrats, a reduced Ih voltage-dependent activationresulting from a subunit shift in the expressionof HCN channels (reduced HCN2 and in-creased HCN1) and, hence, decreased sensitiv-ity to cAMP in thalamocortical neurons, was

found in the WAG/Rij strain (Budde et al.2005; Kuisle et al. 2006); loss of neocorticalIh and HCN1 expression paralleled the onsetof spontaneous absence seizures (Kole et al.2007). In both models, the genetic etiology ofthe epilepsy phenotype is probably multifacto-rial, yet involves dysregulation of HCN channelexpression.

Deletion of the HCN1 gene does not pro-duce an epileptic phenotype; however, HCN1knockout (KO) mice had reduced thresholdto seizures induced by electrical stimulation(amygdala kindling) and also by the chemocon-vulsants kainate or pilocarpine (Huang et al.2009; Santoro et al. 2010). HCN1 KO micewere more susceptible to seizure-related death(irrespective of model used) as compared withwild-type controls. These studies support ananti-excitatory or seizure-protective role ofHCN1. However, whereas knockout studiesare powerful, their interpretation should con-

*

YSYALFKAMSHMLCIGYG

HCN1

COOH

CNBD

C-linker

mRNA levels Ctrl

Ctrl1.4

1.2

1.0

0.8

HC

N m

RN

A le

vels

*0.6

0.4

0.2

0.0

HCN1

HCN2

Seizure

Seizure

Protein levelsExpression following seizure

HisIntracellular

S1 S2 S3

Extracellular

Structure

S4 S5 S6

SF

Phelix

H+NH2 cAMP

Altered channel assembly ratio following seizure

Seizure

HCN2

HCN1/2

+++

++++

Figure 1. Abnormal hyperpolarization-activated cyclic nucleotide-gated ion (HCN) channel regulation andassembly following seizures. HCN channel subunits consist of six transmembrane segments (top left). Thecytoplasmic carboxyl terminus contains a 120-amino-acid cyclic nucleotide-binding domain (CNBD).HCN1 messenger RNA (mRNA) and protein levels are significantly reduced in the hippocampus followingseizures in many animal models of epilepsy; HCN2 levels do not alter appreciably (top right). Altered HCNchannel assembly following seizures may result from a reduction of HCN1 subunits (bottom). SF, Silencer factor;cAMP, cyclic adenosine 30, 50-monophosphate.

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sider potential confounders. In view of thecomplex mechanisms regulating HCN channelexpression, heteromeric assembly and traffick-ing, the potential effects of deletion of a specificHCN channel isoform on the others requiresconsideration. For example, careful analysisshould be performed to detect compensatoryexpression of other HCN channels, which mayresult from loss of one channel. Although globalanalyses of hippocampus or cortex failed touncover compensatory changes in HCN2 (San-toro et al. 2010), Brewster et al. (2006) founda significant increase in HCN2 expression atboth the mRNA and protein level within pyra-midal neurons of hippocampal area CA1 inHCN12/2 mice. Intriguingly, immunohisto-chemistry suggested enhanced trafficking ofHCN2 channels to dendrites of CA1 pyramidalcells. This compensatory increase in HCN2 ex-pression in HCN1 null mice may generate den-dritic Ih and restore the role of Ih in reducingexcitability.

HCN CHANNELS AND EPILEPSY: HUMANSTUDIES

HCN Expression and Function inHippocampus from Resected Patient Tissue

In resected hippocampal tissue from patientswith temporal lobe epilepsy, there were en-hanced levels of HCN1 expression and dendriticlocalization in the granule cells of the dentategyrus (DG) in patients with mesial temporalsclerosis (MTS) (Bender et al. 2003). Separately,Surges et al. (2012) found enhanced Ih in theseDG neurons from patients with MTS comparedwith those without MTS, and concordant in-creased HCN1 mRNA expression. Similarchanges were found in DG neurons from epi-leptic rats induced with the pilocarpine model,with augmented HCN1 expression and Ih thatmirrored the human phenotype. Given the im-portance of Ih in attenuating postsynaptic po-tentials at dendrites and limiting their spread inpyramidal neurons of CA1 region, this up-reg-ulation of HCN1 and Ih in granule cells of thedentate gyrus may be a protective mechanismresulting in controlled dentate gyrus gating.

Further evidence of altered Ih in human epilepsywas shown in studies of tissue from neocorti-cal resections. In pyramidal neurons from pa-tients with a high presurgical seizure frequen-cy, Ih was reduced compared with those withrelatively lower seizure frequency (Wierschkeet al. 2010). Because altered expression ofHCN channels in human hippocampal tissuecan only be analyzed in people with existingepilepsy, it is difficult to say whether alteredHCN channel expression is a cause or conse-quence of epilepsy.

Human Mutations in HCN Channelsand Their Role in Epilepsy

Altered HCN channel expression and function,and the demonstration of a causal role of thesealterations in experimental models of epilepto-genesis promote the question of a potential roleof mutations in HCN channels in human epi-lepsy. Thus far, Mendelian-inherited epilepsyhas not been shown to arise from HCN channelmutation. However, several studies have shownthe association between HCN channel muta-tion and human genetic epilepsy. Tang et al.(2008) undertook the first study mapping mu-tations in HCN channels in patients with idio-pathic generalized epilepsy (IGE), and this anal-ysis uncovered several functional variantswithin HCN1 and HCN2; however, the impactof these variants on channel function were notfully understood. A study that screened patientswith febrile seizures and the defined syndromegeneralized epilepsy with febrile seizures plus(GEFSþ) uncovered a triple proline deletionin HCN2; when recombinant channels were ex-ogenously expressed, the magnitude of the re-sulting Ih was 35% larger than with wild-typechannels (Dibbens et al. 2010). However, be-cause this gene variant did not strictly cosegre-gate with an epilepsy phenotype (being foundin unaffected individuals as well), it is notclearly causative of disease. Another study thatscreened families with epilepsy for mutations inHCN1 and HCN2 found a recessive loss-of-function point mutation in HCN2 in a patientwith sporadic IGE (DiFrancesco et al. 2011).The mutation (E515K) was located within a



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region of the channel known to affect gating,and subsequent functional analysis revealedthat the homomeric mutant channel inhibitedfunction by causing a large hyperpolarizingshift of activation along with slowed activationkinetics. This was the first evidence in humansof a loss-of-function point mutation in HCN2,which may contribute to generalized epilepsywith recessive inheritance.

An intriguing recent association betweenHCN channel mutation and catastrophic earlyepilepsy emerged from a comprehensive studyon a European population. This study employedwhole exome sequencing on parent–child triosthat included probands with early infantile ep-ileptic encephalopathy (Nava et al. 2014), un-covering six different heterozygous mutationsin HCN1. The mutations identified in this studyaffected highly conserved amino acids and wereall located on intracellular portions of the chan-nel. Affected individuals presented with simi-lar phenotypes; however, functional analysis ofthese mutations revealed divergent effects onHCN channel function. The investigators ex-plored this further by coexpressing heterozy-gous mutant channels with wild-type channels,and found that most mutated channels hada dominant negative effect on wild-type chan-nels. The study also found a high level of se-quence conservation and low frequency ofcopy number variation among control popula-tion, suggesting that the conservation of HCNchannels is essential for their appropriate func-tion. Recently, Nakamura et al. (2013) uncov-ered a mutation in HCN2 that may contributeto hyperexcitability and specifically to febrileseizures in children. The relevant mutationwas predicted to replace a residue in the intra-cellular amino terminus. Together, these humanstudies provide support for the role of abnormalHCN channel function in seizures and epilepsy.

SUMMARY

The HCN-regulated ion channels that conductIh have crucial and diverse roles in normal phys-iology. Specifically, they contribute to regula-tion of neuronal and network excitability. Theseroles position HCN channels, and specifically

their aberrant expression, trafficking, posttrans-lational modification, and interactions withother proteins as key targets in understandingthe hyperexcitability found in epilepsy. To date,some of the molecular mechanisms of HCNchannelopathy in both genetic and acquired ep-ilepsy have been dissected, yet there is much tolearn about this ion channel regulation in epi-lepsy. Importantly, the study of HCN channelshas broader implications, because these chan-nels represent an ideal model system in which toinvestigate the interplay of diverse ion channelsand signaling cascades and their potential rolesin a variety of epilepsies. It is hoped that thesemultiple signaling pathways may represent po-tential novel therapeutic targets for reversingabnormal channel expression and function(“channelopathy”) not only of the HCN chan-nels, but of others. The novel mechanisms un-derlying ion channelopathies in epilepsy offerpromise for treating epilepsy that is refractoryto conventional therapy.

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