REVIEW ARTICLE published: 13 September 2013 CELLULAR NEUROSCIENCE doi: 10.3389/fncel.2013.00134 K+ channelepsy: progress in the neurobiology of potassium channels and

Maria Cristina D’Adamo 1,2*, Luigi Catacuzzeno 3, Giuseppe Di Giovanni 2,4, Fabio Franciolini 3 and Mauro Pessia 1,2*

1 Faculty of Medicine, Section of Human Physiology, Department of Internal Medicine, University of Perugia, Perugia, Italy 2 Istituto Euro Mediterraneo di Scienza e Tecnologia, IEMEST, Palermo, Italy 3 Dipartimento di Biologia Cellulare e Ambientale, Università di Perugia, Perugia, Italy 4 Department of Physiology and Biochemistry, University of Malta, Msida, Malta

+ Edited by: K channels are important determinants of seizure susceptibility. These membrane Roberto Di Maio, University of , encoded by more than 70 , make the largest group of ion channels that Pittsburgh, USA fine-tune the electrical activity of neuronal and non-neuronal cells in the brain. Their Reviewed by: ubiquity and extremely high genetic and functional diversity, unmatched by any other ion Enrico Cherubini, International + School for Advanced Studies, Italy channel type, place K channels as primary targets of genetic variations or perturbations + Lan Xie, OVG-University, Germany in K -dependent homeostasis, even in the absence of a primary channel defect. It is + *Correspondence: therefore not surprising that numerous inherited or acquired K channels dysfunctions Maria Cristina D’Adamo and Mauro have been associated with several neurologic syndromes, including epilepsy, which often Pessia, Faculty of Medicine, Section generate confusion in the classification of the associated diseases. Therefore, we propose of Human Physiology, Department + + of Internal Medicine, University of to name the K channels defects underlying distinct as “K channelepsies,” + Perugia, P.leGambuli, Edificio and introduce a new nomenclature (e.g., Kx.y-channelepsy), following the widely used K D - Piano 1, 06132 San Sisto, channel classification, which could be also adopted to easily identify other Perugia, Italy + 2+ − involving Na (e.g., Navx.y-phenotype), Ca (e.g., Cavx.y-phenotype), and Cl channels. e-mail: [email protected]; + [email protected] Furthermore, we discuss novel genetic defects in K channels and associated proteins that underlie distinct epileptic phenotypes in humans, and analyze critically the recent progress in the neurobiology of this disease that has also been provided by investigations on valuable animal models of epilepsy. The abundant and varied lines of evidence discussed here strongly foster assessments for variations in genes encoding for K+ channels and associated proteins in patients with idiopathic epilepsy, provide new avenues for future investigations, and highlight these proteins as critical pharmacological targets.

Keywords: Potassium channels: [Kv1, Kv2, Kv3, Kv4, Kv8, Kv11(HERG), KCa1.1,Kvβ1, Kvβ2, KChIP LGI1, Kir1-Kir7 (GIRK, KATP )], temporal lobe epilepsy, autism–epilepsy, channelopathies

INTRODUCTION 2013). Their opening and resulting outward K+ flux dampen Epilepsy is a brain disorder due to abnormal firing of neu- neuronal excitability and therefore they are viewed as inhibitory ronal networks in the brain that often causes convulsions, muscle channels. However, contrary to this general notion, increased spasms, and loss of consciousness. Seizures sometimes cause K+ channel activity may also result in enhanced cell excitabil- brain damage, particularly if they are severe. More than 2 million ity. Hence, K+ channels are critical for neuronal excitability,as people in the United States—about 1 percent—have experienced they control the resting membrane potentials and enable rapid an unprovoked seizure or been diagnosed with epilepsy. For about repolarization of the action potentials. Moreover, they are essen- 80 percent of those diagnosed with epilepsy, seizures can be tial effectors of neurotransmitter-mediated signaling, regulator of controlled pharmacologically, or treated surgically. However, the Ca2+ homeostasis and cell survival. To fulfill these pivotal func- rest of people with epilepsy—intractable epilepsy—will continue tions efficiently, K+ channels are found in virtually every cell to experience seizures even with the best available treatment. of the human body, are distinguished by being the largest and Although the causes of epilepsy are numerous, the fundamental most diverse class of ion channels, and are encoded by more disorder is secondary to abnormal synchronous discharges of a than 70 genes (http://www.genenames.org/genefamily/kcn.php). network of neurons, either due to neuronal membrane instabil- An additional reason for their large diversity resides in the fact ity, or an imbalance between excitatory and inhibitory influences. that they form macromolecular complexes, involving several pro- Neurons store and convey information in the form of electri- teins. The need for such a large number of K+ channels remains cal impulses generated by ion channels. Neuronal excitability unclear. + can be controlled by both the intrinsic activity of K channels In the past few years, several types of epilepsies have and the receptors-mediated modulation of their activity (Pessia been associated to dysfunction of K+ channels, resulting from et al., 1994; Imbrici et al., 2000; Pessia, 2004; D’Adamo et al., in their encoding genes (Table 1), which appear prime

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elements potentially underlying idiopathic epilepsy. Indeed, the The predicted 496 amino acids of the Kv1.1 α subunit form extremely high molecular and functional diversity of K+ chan- six transmembrane segments (TM) with the N- and C-termini nels, unmatched by any other types of channels, places them residing inside the cell. TM5, TM6, and the H5 loop linking them (by statistical probability alone) as primary targets of genetic contribute to the ion-conducting pore, and the GYG residues, that variations. Besides the intrinsic K+ channels’ defects asso- reside within the loop, control the K+ selectivity of the channel. ciated with epilepsy, it is increasingly clear that also disrup- The TM4 segment of each Kv1.1 α subunit is made of regularly tion/modification in K+ channel properties, even in the absence spaced positively charged arginines and lysines and embodies the of a primary channel defect, may underlie increased susceptibil- main voltage-sensor region that opens the channel by undergoing ity to seizures. The association between K+ channel dysfunctions a conformational rearrangement upon membrane depolarization and epileptic phenotypes is also confirmed by a multitude of (Pessia, 2004). The full crystal structure, provided for a Kv chan- animal models of epilepsy, that is, animals carrying K+ channel nel, confirmed that this channel is composed of four homologous mutations or genetic manipulations and displaying spontaneous pore-forming α subunits (Jiang et al., 2003a,b). The description seizures or increased susceptibility to stimulus-induced seizure of the membrane-delimited Kv channel structure, T1 domain and (Table 2). The extremely high diversity of K+ channels and the β subunits allowed elucidation of many biophysical mechanisms numerous variations identified in their genes often generate con- controlling channel function. The Kv1 family members exhibit fusion in the classification of the associated diseases. Therefore, diverse expression patterns in the central and peripheral nervous we propose to name the K+ channels defects underlying dis- system and are found tightly clustered within distinct neuronal tinct epilepsies as “K+ channelepsies,” and offer a new classifica- compartments (Trimmer and Rhodes, 2004). Kv channels reg- tion according to a widely used K+ channel nomenclature (e.g., ulate the duration of action potentials, modulate the release of + KVx.y). Moreover, here we discuss the different aspects of K neurotransmitters, control the excitability, electrical properties, channels dysfunctions underlying distinct epileptic phenotypes and firing pattern of central and peripheral neurons (Pessia, and describe the recent progress in the neurobiology of seizure 2004). Moreover, the activity of Kv channels can be dynami- susceptibility in animal models of epilepsy. Comprehensive cally modulated by several events, including neurotransmitter- knowledge of the neurobiological processes altered by K+ channel stimulated biochemical cascades (Imbrici et al., 2000; D’Adamo defects is a pivotal step to identify original therapeutic solutions et al., 2013). Knowledge of their precise targeting and neuro- for this devastating disease. Full understanding of how mutations physiological functions has important implications for defining in K+ channels give rise to distinct human and animal epilep- the roles played by each Kv channel type in the pathophysiology tic phenotypes requires a basic knowledge of their molecular of epilepsy. features, expression pattern, and physiological roles. Thus, brief + overviews on these topics for each K channel subfamily have Kv1.1 CHANNELEPSY been included. Episodic ataxia type 1 (EA1) [OMIM 160120] is a -like K+ channels disease characterized by constant myokymia and + VOLTAGE-GATED K CHANNELS AND CHANNELEPSY dramatic episodes of spastic contractions of the skeletal muscles Voltage-gated K+ channels (Kv) are generally closed at the rest- of the head, arms, and legs with loss of both motor coordi- ing membrane potential of nerve cells (ca.–70 mV) and open nation and balance (D’Adamo et al., 2012). EA1 was clearly following membrane depolarization. At a single channel level, described during the mid ‘70s by van Dyke and colleagues who membrane depolarizations elicit channel opening and closing (a first reported electroencephalographic (EEG) recordings charac- process named gating) visible as upwards and downwards deflec- terized by runs of paroxysmal slow waves and generalized motor tions of current trace (Pessia, 2004). The first Kv channel was seizures in the proband’s mother (van Dyke et al., 1975). The sub- cloned from the Shaker mutant of Drosophila melanogaster in sequent genetic analysis revealed that the individuals displaying 1987 (Tempel et al., 1987). The human ortholog of Shaker K+ epilepsy carried the F184C in their KCNA1 gene that channel is encoded by the gene KCNA1(Kv1.1). Since the first profoundly altered the channel’s properties (Browne et al., 1994; cloning, several other genes encoding for Kv channels have been Adelman et al., 1995). Confirmations of an increased suscepti- identified from many different species. Based on sequence relat- bility to seizures in EA1 came from several subsequent studies edness, Kv channels have been classified in subfamilies by using (Table 1). Isolated photosensitive generalized tonic–clonic seizure the abbreviation Kvy.x (Chandy and Gutman, 1993). According (Imbrici et al., 2008) and abnormal EEGs have been observed to this standardized nomenclature Shaker-related channels have in individuals with EA1 (Zuberi et al., 1999). EEGs may be been classified in the subfamily Kv1.x and each member num- characterized by intermittent and generalized slow activity, fre- bered Kv1.1 through Kv1.8. The same criteria have been used quently intermingled with spikes. Zuberi et al. (1999) described a to classify channels related to the Drosophila subfamilies Shab 3-year-old boy who presented with an ictal EEG with rhythmical (Kv2.1 and Kv2.2), Shaw (Kv3.1 to Kv3.4), and Shal (Kv4.1 to slow-wave activity over the right hemisphere, becoming spike- Kv4.3). These channels may exist as homomers, whenever four and-wave complexes that then spread to the left hemisphere. identical α-subunits are assembled. However, different types of Neuronal circuit dysfunctions within the hippocampus have been α-subunits may heteropolymerize to form channels with func- postulated to play a role in seizures and cognitive dysfunctions tional and pharmacological properties that are different from the associated with EA1. Indeed, the hippocampus is a major brain parental homomeric channels (Isacoff et al., 1990; Ruppersberg region of the limbic system which plays an important role in et al., 1990). the consolidation of information and in spatial memory, and it

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Table 1 | Human K+ channelepsies.

Channel Gene/ Expression in brain Epilepsy type Gene References regions relevant to mutation/channel epilepsy dysfunction

KCNA1/Kv1.1 (pore Axons/terminals of Generalized and partial Loss-of-function Assaf and Chung, 1984; forming α subunit) hippocampal neurons seizures associated to mutations generally Browne et al., 1994; (Shaffer collateral axons EA1 associated with Adelman et al., 1995; and mossy fibers reduced current D’Adamo et al., 1998, contacting CA3 amplitudes; positive 1999; Zuberi et al., neurons); hippocampal shift of the activation 1999; Geiger and interneurons of hilus V1/2; increased Jonas, 2000; Cusimano and CA1; neocortical sensitivity to Zn2+ et al., 2004; Imbrici pyramidal neurons inhibition et al., 2006, 2007, 2008; Guan et al., 2006

KCNAB2/Kvβ2(β Widely expressed in Severe epilepsy Allele deletion/ Heilstedt et al., 2001 accessory subunit for cerebral cortex and including infantil haploinsufficiency Kv1 channels) hippocampus spasms

LGI1 (Accessory Neocortex and Autosomal dominant E383A, frameshift Kalachikov et al., 2002; protein for Kv1 hippocampus lateral temporal lobe with protein Morante-Redolat et al., channels) epilepsy truncation/Mutated 2002 LGI1 does not prevent Kvβ1-mediated Kv1 channel inactivation, a function

channels performed by the WT

+ protein

KCND2/Kv4.2 (IA pore Dendrites of Temporal lobe epilepsy Truncated Kv4.2 Singh et al., 2006 forming α subunit) hippocampal neurons subunit/attenuated IA current density

Voltage-gated K KCNV2/Kv8.2 (silent Pyramidal neurons and Febrile and afebrile R7K, M285K/Reduction Jorge et al., 2011 subunit associating principal excitatory partial seizures; of Kv2.1 mediated with Kv2 channels) neurons of the epileptic current; M285K impairs pyramidal cell layers encephalopathy the voltage- and the dentate gyrus; dependence of the cortex, with high levels channel of transcript in Layers 2/3 and 5

KCNQ2-3/ Kv7.2-3 (M Widely expressed in Benign familial neonatal Five– insertion Biervert et al., 1998; current pore forming α brain at neuronal cell convulsions deleting more than 300 Charlier et al., 1998; subunit) bodies amino acids from the Schroeder et al., 1998; KCNQ2; missense Singh et al., 1998 mutations in critical regions for KCNQ3 channel function / Reduced KCNQ current amplitudes

KCNH2/Kv11.2 (HERG Widely expressed in Epilepsy associated Loss-of-function Keller et al., 2009; channel pore forming α brain with type 2 long QT mutations Omichi et al., 2010; Tu subunit) syndrome et al., 2011; Zamorano-León et al., 2012

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Table 1 | Continued

Channel Gene/protein Expression in brain Epilepsy type Gene References regions relevant to mutation/channel epilepsy dysfunction

KCNMA1/KCa1.1 (BK Axons and pre-synaptic Generalized epilepsy D434G/ Increase of Du et al., 2005; channel pore forming α terminals of excitatory and paroxysmal channel open Díez-Sampedro et al., subunit) neurons of cortex and diskynesia probability and calcium 2006; Lee and Cui,

hippocampus dependence of KCa1.1 2009; Yang et al., 2010 expressed alone or with channels

+ KCaβ1,KCaβ2,orKCaβ4; loss-of-function of

KCa1.1/KCaβ3–mediated currents

-dependent K KCNMB3/K β Widely expressed at Idiopathic generalized Loss-of-function of Behrens et al., 2000;

+ Ca 3 2 (accessory protein for low levels in brain epilepsy KCa1.1/KCaβ3-mediated Hu et al., 2003; Lorenz Ca KCa1.1 channels) currents et al., 2007

KCNJ2/Kir2.1 (pore Hippocampus, caudate, Seizures associated to Loss-of-function Haruna et al., 2007; forming α subunit) putamen, nucleus the Andersen Tawil mutations with Chan et al., 2010 accumbens; to lower Syndrome (ATS) dominant-negative levels in habenula and effects amygdala

KCNJ10/Kir4.1 (pore Oligodendrocytes and Seizure susceptibility R271C missense Buono et al., 2004; forming α subunit) astrocytes surrounding variation; no alteration Connors et al., 2004; synapses and blood in the biophysical Shang et al., 2005 vessels, mainly in the properties of the cortex, thalamus, channel when channels

+ hippocampus, and heterologously brainstem expressed

Epilepsy associated to Loss-of-function Bockenhauer et al., EAST syndrome recessive mutations 2009; Scholl et al., 2009

Epilepsy associated to R18Q, V84M, Sicca et al., 2011 autism spectrum gain-of-function of Inwardly-rectifying K disorders (ASDs) Kir4.1 and Kir4.1/Kir5.1-mediated current

KCNJ11/Kir6.2 (KATP Hippocampus (principal Developmental delay, Gain-of-function Karschin et al., 1997; channel pore forming α neurons, interneurons, epilepsy and neonatal mutations leading to Hattersley and Ashcroft, subunit) and glial cells); diabetes mellitus decreased channel 2005

ABCC8/SUR1 (KATP neocortex, entorhinal (DEND syndrome) inhibition by ATP,or channel accessory and piriform cortex enhanced Mg2+- regulatory subunit) nucleotide-induced activation

The table depicts the principal inherited human channelepsies caused by mutations in K+ channel α subunits or associated accessory proteins. For each channelepsy, information about the name of the mutated gene/protein, its expression in brain regions relevant to the pathology, type of epilepsy and association with other known syndromes, and dysfunction in channel behavior caused by the mutations are reported. is often the focus of epileptic seizures. In rodent hippocampus, of these subunits, regulates the activity-dependent spike broad- Kv1.1, Kv1.2, and Kv1.4 are found in Schaffer collateral axons ening of hippocampal mossy fiber boutons and, consequently, and are highly expressed in axons and terminals of the medial the amount of neurotransmitter released during high-frequency perforant path in the middle third of the molecular layer of stimuli (Geiger and Jonas, 2000). Mutations associated with EA1 the dentate gyrus. In particular, Kv1.1, Kv1.4, and Kvβ1.1 sub- profoundly alter the function of heteromeric channels composed units are expressed in mossy fiber boutons (swellings of mossy of Kv1.1, Kv1.2, Kv1.4, and Kvβ1.1 subunits (D’Adamo et al., 1999; fiber axons)thatformen passant synapses with pyramidal neu- Imbrici et al., 2006) that likely contributes to seizures suscep- rons in CA3. The macromolecular channel complex, composed tibility and cognitive symptoms (Imbrici et al., 2006)inEA1.

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Table 2 | Animal models of K+ channelepsies.

Channel Gene/protein Animal model/channel Epilepsy phenotype Functional effects of References disfunction mutation on neurons relevant to epilepsy

Kcna1/Kv1.1 (pore Kv1.1V 408A/+ mice/ EA-1 unknown Cf. Ta b l e 1 for WT forming α subunit) mutation that alters the expression; unknown biophysical properties of the channel

Kv1.1−/− knockout mice Spontaneous seizures Hippocampus with Smart et al., 1998; Rho resembling human neural loss, astrocytosis, et al., 1999 temporal lobe epilepsy and mossy fiber sprouting; mossy fiber stimulation mediates long-latency epileptiform burst discharges; mossy fibers and medial perforant path axons were hyperexcitable and produced greater pre- and post-synaptic responses with reduced paired-pulse ratios

Kv1.1S309T /+ rats/80% neuromyotonia and Cortical and hippocampal Ishida et al., 2012 smaller current spontaneous convulsive EEG with aberrant large

channels amplitudes with seizures aggravated by spike activity associated

+ dominant-negative stress with falling-down effects behavior, low-voltage fast wave discharges during the tonic stage, spike-and-wave

Voltage-gated K discharges (2 Hz) during the clonic convulsive stage. Behavioral phenotypes and abnormal discharge patterns similar to other rodent models of temporal lobe epilepsy

mceph/mceph mice, Running seizures, Increased brain volume Donahue et al., 1996; carrying a 11-basepair complex partial seizures and hypertrophic brain Petersson et al., 2003 deletion in the Kcna1 and post-anesthetic cells; hippocampal gene. The mutation tonic-clonic seizures hyperexcitability leads to a frame shift and consistent with limbic to a premature stop status epilepticus codon

Adar2−/− mice Increased susceptibility Adenosine deaminase Higuchi et al., 2000; to epileptic seizure (Adar2) acting on Kv1.1 Bhalla et al., 2004 mRNA and leading to a gain-of-function of the resulting current (increased amplitude and faster recovery from inactivation). Adar2 also edits the mRNA of AMPA glutamate receptors

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Table 2 | Continued

Channel Gene/protein Animal model/channel Epilepsy type Functional effects of References disfunction mutation on neurons relevant to epilepsy

Kcna2/Kv1.2 (pore Kv1.2−/− knockout mice Spontaneous generalized WT Expression: mainly Brew et al., 2007 forming α subunit) seizures overlapping with that of Kv1.1 channels; fibers and neuropil, but not somata, neocortex; synaptic terminals of entorhinal afferents. Strongly expressed in axon initial segment, where they partecipate to action potential generation

Kcnab2/Kvβ2(β subunit Kvβ2−/− knockout mice/ Increased neuronal Cf. Ta b l e 1 for WT McCormack et al., 2002; for Kv1 channels) β2 promotes the excitability, occasional expression; Connor et al., 2005; trafficking of Kv1.1 and seizures deficits in associative Perkowski and Murphy, Kv1.2 to the membrane learning and memory; 2011 surface reduction in the slow afterhyperpolarization and concomitant increase in excitability of projection neurons in the lateral nucleus of the amygdala

Kchip2 (Accessory Kchip2−/− knockout Increased susceptibility WT Expression: apical Wang et al., 2013

subunit for Kv4 channels) mice/ Reduced IA current to seizure induced by dendrities of density and slowed kindling hyppocampal pyramidal recovery from cells inactivation in Chronic hyperexcitability hyppocampal neurons of hyppocampal pyramidal neurons

Lgi1 (Accessory protein Lgi1−/− knockout mice/ Lethal epilepsy; the Cf. Ta b l e 1 for WT Fukata et al., 2010 for Kv1 channels) Kvβ1-mediated Kv1 heterozygous has a expression. channel inactivation is lowered seizure AlackofLgi1 disrupts not prevented, a function thresholds synaptic protein performed in WT mice connection and selectively reduces AMPA receptor-mediated synaptic transmission in the hippocampus

−/− Kcnd2/Kv4.2 (IA pore Kv4.2 knockout mice Enhanced susceptibility Cf. Ta b l e 1 for WT Hu et al., 2006; forming α subunit) to kainate-induced expression. Increased Nerbonne et al., 2008; seizure, but see Hu et al., epileptiform bursting in Barnwell et al., 2009 2006 area CA1

β −/− Kcnb4/KCa 4 (accessory KCaβ4 Temporal cortex seizures WT expression: axons Jin et al., 2000; Raffaelli subunit for KCa1. 1 mice/Gain-of-function of and presynaptic et al., 2004; Brenner channels) KCa1.1-mediated current terminals of shaffer et al., 2005; Shruti et al., collaterals and CA3 2008; Sheehan et al., hippocalpal neurons. 2009 -dependent + channels Higher firing rate of 2 + dental gyrus neurons Ca K

(Continued)

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Table 2 | Continued

Channel Gene/protein Animal model/channel Epilepsy type Functional effects of References disfunction mutation on neurons relevant to epilepsy

Kcnj6/Kir3.2 (GIRK2 Kir3.2−/− knockout mice Spontaneous WT expression: cortex, Signorini et al., 1997 channel pore forming α convulsions and hippocampus, weaker subunit) increased propensity for signal in thalamic nuclei generalized seizures; and amygdaloid nuclei; more susceptible to reduced GIRK1 pharmacologically- expression in brain induced seizure

Weaver (w/w) mice, epileptic seizures Neurodegeneration; Patil et al., 1995; G156S/alteration of the calcium oveload within Slesinger et al., 1996 K+ selectivity of the cells, reduced GIRK1

channels channel expression in brain + Kcnj10/Kir4.1 (pore Kir4.1−/− knockout mice Stress-induced seizures WT expression: Neusch et al., 2001; forming α subunit) oligodendrocytes and Djukic et al., 2007 astrocytes sourronding synapses and blood vessels in cortex, thalamus, hyppocampus, braistem Inwardly-rectifying K No membrane depolarization is observed in astrocytes + following [K ]o increase by neuronal activity

DBA/2 mouse strain, Greater susceptibility to Potassium and glutamate Ferraro et al., 2004; T262S missense induced seizures buffering by cortical Inyushin et al., 2010 variation resulting in a compared to the astrocytes is impaired barium-sensitive Kir C57BL/6 strain currents in astrocytes substantially reduced; No alteration in the biophysical properties of the channel

−/− Kcnj11/Kir6.2 (KATP Kir6.2 knockout mice High-voltage sharp-wave Cf. Ta b l e 1 for WT Yamada et al., 2001 channel pore forming α bursts EEG expression; subunit) Substantia nigra neurons are depolarized by hypoxia (WT neurons are instead hyperpolarized)

The table depicts the principal animal models of epilepsy caused by mutations in K+ channel α subunits or associated accessory proteins. For each animal model, information about the name of the mutated gene/protein, type of epileptic phenotype, dysfunction in channel behavior caused by the mutation, and functional effects of the mutation are reported.

Notably, epileptiform brain activity has also been associated with several folds the Zn2+ sensitivity of these channels (Cusimano + + intracranial administration of Zn2 salts, and changes in Zn2 et al., 2004; Imbrici et al., 2007). Whether Zn2+ plays a role in modulation of GABA receptors have been implicated in the eti- triggering epilepsy-like symptoms in EA1 remains an intriguing + ology of epilepsy. Zn2 is released from mossy fiber terminals hypothesis. A murine model that recapitulates the EA1 phenotype in the hippocampus, and from the basket cell terminals of the (mKv1.1V408A/+) has been generated by inserting in the mouse cerebellum (Assaf and Chung, 1984) where Kv1 channel activ- Kcna1(mKv1.1) a very conservative valine to alanine substitu- ity likely is subjected to Zn2+ modulation. Indeed, homomeric tion (V408A) previously identified in patients (Herson et al., and heteromeric channels containing Kv1 subunits are inhib- 2003; Brunetti et al., 2012, Table 2). Although data concern- ited by extracellular Zn2+, and a distinct EA1 mutation increases ing the mKv1.1V408A/+ are not yet available, the role of Kv1.1

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channels in the neurobiology of epilepsy has been investigated phenotype including running seizures, complex partial seizures by using Kv1.1 knockout mice (mKv1.1−/−). The hippocam- and postanaesthetic tonic-clonic seizures (Donahue et al., 1996, pus of these animals displays morphological characteristics typ- Table 2). Remarkably, an 11-basepair deletion in the Kcna1 gene ical of epilepsy, with neural loss, astrocytosis, and mossy fiber of mceph/mceph mice has been identified (Petersson et al., 2003). sprouting (Rho et al., 1999). Moreover, mKv1.1−/− also exhibits The mutation leads to a frame shift and a premature stop codon frequent spontaneous seizures throughout adult life, although that was predicted to truncate the protein at amino acid 230 (out the intrinsic passive properties of CA3 pyramidal cells are nor- of 495). Therefore, mceph/mceph mice express Kv1.1 subunits mal (Table 2). Antidromic action potentials were recruited at lacking the last five TMs and the C-terminal domain: The absence lower thresholds in mKv1.1−/− slices, and mossy fiber stimu- of Kv1.1 channels with intact C-terminal domains was confirmed lation triggered synaptically-mediated long-latency epileptiform by Western blotting analysis of whole protein extracts from brain. burst discharges. These data indicate that loss of Kv1.1 results Electrophysiological investigations from mceph/mceph brain slices in increased excitability in the CA3 recurrent axon collateral revealed hippocampal mceph/mceph brain slices revealed hip- system, perhaps contributing to the limbic and tonic–clonic com- pocampal hyperexcitability consistent with limbic status epilep- ponents of the observed epileptic phenotype of EA1 (Smart et al., ticus (SE) C-teminal domain of Kv1.1 channels (R417stop) has 1998). Recently, in vitro extracellular recordings were performed also been found in a EA1 proband displaying episodes of ataxia by using a multielectrode array to characterize spontaneous precipitated by exercise, stress, startle or high temperature occur- sharp waves and high frequency oscillations in mKv1.1−/− hip- ring after a hot bath or when using a hairdryer but, absence of pocampi. This study showed that the mossy fibers and medial epilepsy (Eunson et al., 2000). perforant path axons of mKv1.1−/− were hyperexcitable and pro- Kv1.2 knockout mice display increased seizure susceptibility duced greater pre- and post-synaptic responses with reduced (Brew et al., 2007, Table 2). It should be recalled that Kv1.1 and paired-pulse ratios. Microdissection of mossy fibers and per- Kv1.2 are closely coupled K+ channel subunits, as they form forant path in mKv1.1−/− hippocampal slices ameliorated the heteromeric channels in several brain regions. Indeed, biochemi- abnormal oscillatory pattern and improved spike timing. In con- cal and electrophysiological studies have shown that Kv1.1/Kv1.2 trast, blockade of Kv1.1 channels with dendrotoxin-K reproduced channels control neuronal excitability, action potentials propaga- these effects in WT slices. These findings suggest that loss of tion and synaptic transmission. Notably, EA1 mutations alter the Kv1.1 enhances synaptic neurotransmitter release in the CA3 function of heteromeric channels composed of Kv1.1 and Kv1.2 region, which reduces spike timing precision of individual neu- subunits (D’Adamo et al., 1999). In conclusion, these investiga- rons, leading to disorganization of network oscillatory activity tions with animal models of Kv1.1 channelepsy highlighted the and promoting the emergence of fast ripples (Simeone et al., crucial brain regions that are likely the site of origin of abnormal 2013). discharges in EA1 and the relevant mechanisms underlying their N-ethyl-N-nitrosourea (ENU) mutagenesis has been widely susceptibility to seizures. used to generate animal models of human diseases. An ENU- mutagenized rat strain has been recently generated and named ROLE OF RNA EDITING IN Kv1.1 CHANNELEPSY “autosomal dominant myokymia and seizures” (ADMS) rats Kv1.1 mRNA is target for enzymatic deamination by adenosine (Ishida et al., 2012). Genetic analysis of these animals resulted deaminase acting on RNA (ADAR2). Knockout mice for the in the identification of the missense mutation S309T in the ADAR2 gene are prone to epileptic seizures and die within a few voltage-sensor domain of Kv1.1 channels (rKv1.1S309T/+). This weeks after birth (Higuchi et al., 2000, Table 2). Kv1.1 editing by heterozygous mutation resulted in 80% smaller current ampli- ADAR2 results in channels with an I400V exchange in the S6 seg- tudes with dominant-negative effects (Table 2). From 16 weeks ment (Kv1.1I400V). In vitro,anincreaseinincreaseinKv1.1I400V of age severe periodic seizures were observed, and by 30 weeks editing increases K+ outward current upon membrane depo- of age, 84% of rKv1.1S309T/+ had died. Cooling induced severe larization and accelerates recovery from inactivation at negative neuromyotonia, ataxia and aberrant spike-and-wave discharges membrane potentials (Bhalla et al., 2004). Interestingly, increased (2–3 Hz) associated with clonus behaviors. Spontaneous convul- levels of Kv1.1I400V editing were found in chronic epileptic rats. It sive seizures from 10 to 16 weeks of age were aggravated by stress has also been reported a reduced ability of 4-AP to trigger seizure- (cage changing or animal handling). Cortical and hippocampal like effects in brain slices dissected from a kainic acid rat model EEG recordings identified aberrant large spike activity associ- of chronic epilepsy (Zahn et al., 2008; Streit et al., 2011). A sim- ated with falling-down behavior, low-voltage fast wave discharges ilar phenomenon was observed in human brain slices of patients detected during the tonic stage, and spike-and-wave discharges with pharmacoresistant TLE (Gabriel et al., 2004). The postulated (2 Hz) detected during the clonic convulsive stage (Ishida et al., ictiogenic mechanism of 4-AP action is its ability to block Kv1 2012). The behavioral phenotypes and abnormal discharge pat- and Kv3 channels, which results in increased transmitter release. terns in rKv1.1S309T/+ are similar to other rodent models of Kv1.1I400V editing results in 4-AP–insensitive homomeric Kv1.1 temporal lobe epilepsy (TLE). Carbamazepine (CBZ) administra- channels, and alters the pharmacology of heteromeric channels tion ameliorated seizures. The videos related to this animal model (Decher et al., 2010; Streit et al., 2011). These findings sug- of EA1 are available online at doi:10.1016/j.brainres.2011.11.023. gest that mRNA editing of Kv1.1 in chronic epilepsy may to the The megencephaly mice, mceph/mceph,arecharacterizedby reorganization of the entorhinal cortex and have anticonvulsive increased brain volume, hypertrophic brain cells and slight effects. The editing of Kv1.1 mRNA could therefore represent a hippocampal astrocytosis. They display a complex behavioral compensatory mechanism in brain areas where epileptic seizures

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originate. TLE, namely spontaneous seizures involving the hip- other hand, seizures in vivo and glutamate in vitro induce a pocampal formation, is the most prevalent refractory epilepsy. rapid surface recruitment of Kv4.2 channels in neurons. Thus, TLE can be sub-classified into mesial, lateral and neocortical. seizure would induce dampening of phasic firing, generated by Mesial TLE (MTLE) is defined by clinic-anatomical observa- glutamatergic synaptic transmission, by enhancing the surface tions and characterized by seizures arising from the hippocampus expression of Kv4.2 channels. Interestingly, mutant LGI1 blocks or parahippocampal structures, and frequent pharmacotherapy this homeostatic neuronal response (Smith et al., 2012). Thus, resistance. A recent screening study identified a significant nega- it seems that convulsants may affect Kv4 currents in different tive correlation between epilepsy duration in patients with MTLE ways and compensatory pathways may be recruited to dampen plus hippocampal sclerosis and the I/V editing site of Kv1.1 chan- hyper-excitability. nels. This may be the result of the epileptic process itself, together One of the most pronounced anatomical effects of TLE, exhib- with the medication history of the patient, and may thus reflect ited in the pilocarpine animal model, is mossy fiber sprouting. compensatory mechanisms to either of these factors (Krestel et al., The expansion of Kv1.4 staining in stratum lucidum of CA3 2013). in pilocarpine-SE animals suggests that expansion of the mossy fiber terminal field, due to SE-induced sprouting, is accompa- Kv4 CHANNELEPSY nied by parallel increases in targeting of Kv1.4 to the newly Kv4 channels underlie the main dendritic A-type Kv currents sprouted mossy fiber axons and terminals. Changes in Kv1.4 in hippocampal neurons and play a critical role in regulating immunoreactivity were observed also in the molecular layer of the extent to which back-propagating action potentials invade the dentate gyrus. In conclusion, variations in A-type Kv1.4- the dendritic tree. They also impact the propagation of synap- containing channels in mossy fiber presynaptic terminals, and tic potentials from the dendritic arbor to the soma (Jerng et al., Kv4.2-containing channels in dentate granule cell and CA1 2004). The relevance of Kv4.2 to epilepsy comes from the iden- dendrites, represent important mechanisms intervening in the tification of a mutation in a patient with TLE, which results in acquisition of the permanent epileptic phenotype in this ani- the expression of a truncated Kv4.2 subunit (Singh et al., 2006, mal model of human TLE and attractive therapeutic targets. Table 1), and the observation that pharmacological blockade of Moreover, these studies highlighted the essential nature of Kv4.2 Kv4 channels is epileptogenic (Avoli, 2001). These studies sup- and the specific contributions of its auxiliary KChIP subunits port the concept that Kv4.2 deficiency may contribute to aberrant (see below) in regulating the seizure susceptibility associated with network excitability and regulate seizure threshold. Intriguingly, epileptogenesis. it has been reported that Kv4.2 knockout mice do not exhibit an overt seizure phenotype (Hu et al., 2006), perhaps due to post- Kv7-M-CHANNELEPSY translational up-regulation of other Kv currents (Nerbonne et al., Five members of the KCNQ gene family have been 2008). A more recent study, however, suggests that loss of Kv4.2 identified (KCNQ1-5) which form homomeric or het- channels is associated with enhanced susceptibility to seizures eromeric K+ channels. In many brain regions, heteromeric after kainate injection (Barnwell et al., 2009, Table 2). KCNQ2(Kv7.2)/KCNQ3(Kv7.3) channels seem the major Systemic administration of the muscarinic agonist pilocarpine determinant of “M” currents that are inhibited by several to rats recapitulates the features of human limbic seizures and neurotransmitters, including acetylcholine (ACh) through the SE. The expression of a number of different K+ channels, includ- muscarinic receptors (Devaux et al., 2004; Pan et al., 2006). + ing Kv (Monaghan et al., 2008)andKCa (BK) channels (Pacheco Functionally, these slow-gating K channels that are open at Otalora et al., 2008) is altered in response to pilocarpine-induced subthreshold voltages, contribute to setting the resting mem- SE. The amplitude of A-type currents in the dendrites of hip- brane potential of neurons, prevent repetitive firing, and control pocampal CA1 pyramidal neurons is reduced in response to spike-frequency adaptation. Indeed, blockade of M-currents pilocarpine-induced seizures (Bernard et al., 2004). In addition is associated with depolarization of the resting membrane to Kv4.2, Kv4.3 and KChIP2 current decrease, pilocarpine-treated potential, and generation of trains of action potentials (Brown rats exhibited staining changes for these proteins in the molecular and Adams, 1980; Delmas and Brown, 2005). Mutations in layer of the dentate gyrus from being uniformly distributed across KCNQ2 or KCNQ3 cause a form of juvenile epilepsy called benign the molecular layer to become concentrated in just the outer two- familial neonatal convulsions (Biervert et al., 1998; Charlier et al., thirds (Monaghan et al., 2008). As a consequence, an increased 1998; Schroeder et al., 1998; Singh et al., 1998, Table 1). The dendritic excitability was found in CA1 pyramidal cell dendrites clinical features of KCNQ2-related benign familial neonatal in response to the same pilocarpine model of TLE (Bernard epilepsy (KCNQ2-BFNE) are characterized by tonic or apneic et al., 2004). In situ hybridization studies revealed that general- episodes, focal clonic activity, or autonomic changes that start ized seizures induced by pentylenetetrazol (Tsaur et al., 1992)or between the second and eighth day of life and spontaneously kainic acid (Francis et al., 1997) also altered the regional hip- disappear between the first and the sixth to 12th month. The pocampal of rat Kv4.2. A decrease of A-current KCNQ2-related epileptic encephalopathy (KCNQ2-NEE)is density in this proximal region of the granule cell dendrite— characterized by multiple daily seizures that begin the first week a location that receives massive aberrant excitatory mossy fiber of life, are mostly tonic, with motor and autonomic features, input following induction of SE and as spontaneous seizures and cease after 9 months to 4 years. Most affected individuals develop—would lower the firing threshold and thus contribute are intellectually impaired (Bellini et al., 1993-2013). Just a 25% to the development of spontaneous recurrent seizures. On the decrease in M-current amplitude is sufficient to drive human

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neurons to epileptogenic levels, and causes neonatal epilepsy in increased CA1 pyramidal neuron excitability under conditions (Schroeder et al., 1998). The clinical severity of the disease may be of high-frequency stimulation (Du et al., 2000). Thus, the Kv2.1 related to the extent of mutation-induced functional K+ channel current reduction, mediated by the inclusion of Kv8.2 subunits in impairment (Miceli et al., 2013). Drugs that enhance neuronal heterotetramers, could regulate the membrane repolarization and M-currents, such as retigabine, represent a valuable therapeutic excitability of hippocampal neurons, contributing to seizure sus- treatment for certain hyperexcitatory diseases, including epilepsy ceptibility. Indeed, mutations in two related silent subunits have (Porter et al., 2012). Flupirtine, a structural analogue of reti- been associated with neurological disorders (Table 1). In partic- gabine, which also activates channels formed by neuronal Kv7 ular Kv8.2 (KCNV2)withepilepsy(Jorge et al., 2011)andKv9.1 subunits, has been shown to be effective in animal models of (KCNS1) with chronic pain (Costigan et al., 2010). Recently, an neonatal convulsion (Raol et al., 2009). Kv7.1 (KCNQ1) channels individual affected by febrile and afebrile partial seizures has are mainly expressed in the heart where they contribute to been reported to carry a genetic variation in KCNV2,inherited termination of the action potential. Mutations in KCNQ1(Kv7.1) from his unaffected mother. This resulted in the substitution of are responsible for one form of long QT syndrome (LQT1) a highly conserved lysine for an arginine (R7K) in the cytoplas- (Wang et al., 1996). However, Kv7.1 channels are also expressed mic amino terminus of Kv8.2 subunits. An additional patient who in the brain. Intriguingly, LQT1 patients exhibit an increased risk inherited a methionine to arginine mutation (M285R) in Kv8.2 of epilepsy, suggesting a relationship between these two diseases subunits from his unaffected mother was likewise identified with (see below). Notably, M-channels are also highly sensitive to an epileptic encephalopathy and with severe refractory epilepsy intracellular Ca2+ variations, being inhibited by Ca2+ with an (Jorge et al., 2011). The pathogenic relevance of these variants IC50 of ∼100 nM in sympathetic neurons (Selyanko and Brown, was assessed by electrophysiological recordings from cells co- 1996; Gamper and Shapiro, 2003). Recently, it has been proposed expressing the human Kv2.1 with Kv8.2 wild-type or its mutated that abnormal [Ca2+]i transients induced by Kv1.1 channel subunit (R7K or M285R). This assay showed that both variants dysfunction may result in repetitive discharges in myelinated suppressed Kv2.1-mediated current more than the wild-type; in nerves (Brunetti et al., 2012). This mechanism may underlie not addition, the M285R impaired the voltage-dependence of the only the neuromyotonic/myokymic discharges typically observed channel. These results suggest that both variants enhance seizure in EA1 individuals, but also their susceptibility to seizures. susceptibility of affected patients by reducing neuronal delayed- The neuronal serum- and glucocorticoid-regulated kinase 1 rectifier K+ channel function in brain regions critically involved (SGK1.1) appears to be a physiological M-current regulator, as in seizure generation and propagation (Jorge et al., 2011). it enhances Kv7.2/3 current levels. Transgenic mice expressing The severity of seizures in mouse models of epilepsy is highly a constitutively active form of SGK1.1 are resistant to kainic dependent on their genetic background. In transgenic mouse acid-induced seizures which occur mainly in the temporal lobe. models of -dependent epilepsy, the phenotype These findings indicate that SGK1.1 activity can regulate neuronal is more severe in SJL/J compared with the C57BL/6J strain excitability through M-current modulation and protects against (Bergren et al., 2005). Interestingly, it has been shown that seizures (Miranda et al., 2013). the hippocampal Kv8.2 (Kcnv2)transcriptis∼3-fold greater in SJL/J compared with the C57BL/6J strain (Jorge et al., 2011). Kv8 CHANNELEPSY: ROLE OF THE SILENT MODIFIERS OF K+ The enhanced availability of Kv8.2 subunits for co-assembling CHANNELS IN EPILEPSY with Kv2.1 would remarkably reduce the surface expression of A number of subunits have been cloned and classified in the K+ the resulting channels in hippocampal neurons of SJL/J mice channel subfamilies Kv6, Kv8, and Kv9. Although they possess the contributing to their greater susceptibility to seizures. hallmarks of Kv subunits they do not appear to form functional In conclusion, these studies implicate Kv8.2 (Kcnv2)asan homomeric K+ channels when expressed alone and, therefore, epilepsy gene in rodents and humans. Moreover, although silent have been named “silent” subunits. However, these proteins do subunits have been mostly ignored since they were first cloned co-assemble with other Kv subunits (e.g., Kv2), and confer dis- a decade or more ago, their potential clinical relevance is now tinct biophysical properties to heteromeric channels Kv2/Kv6, becoming fully evident and therefore represents an attractive new Kv2/Kv8, or Kv2/Kv9. Thus, these gene products are also known avenue of investigation in neurologic channelopathies research. as “silent modifiers”ofKvchannels.Inparticular,Kv8.2(KCNV2) co-assembles with Kv2.1 as a heterotetramer, significantly reduc- Kv11-HERG-CHANNELEPSY ing the surface expression of the resulting channels and influenc- The human ether-a-go-go-related gene (HERG) encodes for ing their biophysical properties. Within the hippocampus, Kv2.1 voltage-gated K+ channels. HERG channels exhibit func- and Kv8.2 co-localize in pyramidal neurons and in the principal tional properties remarkably different from other K+ chan- excitatory neurons of the pyramidal cell layers and the dentate nels (Tristani-Firouzi and Sanguinetti, 2003). They are widely gyrus. Moreover, both are expressed in the cortex, with high lev- expressedinthebrainwheretheycontributetosettingthefre- els of transcript in layers 2/3 and 5 (Allen brain atlas; http:// quency and the discharge stability of neurons, and to adapt- www.brain-map.org). These regions are critically involved in ing their intrinsic properties to signal processing (Pessia et al., seizure generation and propagation. It has been shown that Kv2.1 2008). They also modulate the excitability of dopaminergic and channels contribute significantly to the delayed-rectifier K+ cur- GABAergic neurons (Nedergaard, 2004; Canavier et al., 2007). rents in hippocampal neurons (Murakoshi and Trimmer, 1999). HERG channels are expressed in the heart where they control the Importantly, knockdown of Kv2.1 in hippocampal slices resulted repolarization of ventricular action potentials. Loss-of-function

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mutations in KCNH2 (HERG) cause type 2 long QT syndrome necessary to determine thoroughly how loss or haploinsufficiency (LQT2), a condition in which the induced delayed repolarization of the Kvβ2 gene affects distinct network excitability and causes of the heart following a heartbeat increases the risk of episodes Kvβ2 channelepsy. of sudden death due to ventricular fibrillation. However, LQT syndrome is closely associated with seizure and frequently it is KvLGI1 CHANNELEPSY misdiagnosed as epilepsy (Table 1). Sudden unexpected death The leucine-rich glioma-inactivated-1 (LGI1)isasecretedneu- in epilepsy is the most frequent epilepsy-related cause of death ronal protein, complexed with Kv channels, and highly expressed for which an underlying arrhythmogenic predisposition has been in neocortex and hippocampus. LGI1 mutations—e.g., the point suggested. Several clinical reports have recently described seizures mutation E383A that prevents the neuronal secretion of LGI1—have and arrhythmic events in LQT2 triggered by visual or acous- been found in patients with autosomal dominant lateral tempo- tic stimuli (Keller et al., 2009; Omichi et al., 2010; Tu et al., ral lobe epilepsy (ADLTE), a syndrome characterized by partial 2011; Zamorano-León et al., 2012). Considering that HERG seizures with acoustic or other sensory hallucinations (Kalachikov channels control several neuronal electrical features, including et al., 2002; Morante-Redolat et al., 2002; Fukata et al., 2010, discharge dynamics (Pessia et al., 2008), these clinical findings Table 1). Moreover, loss of Lgi1 in mice causes lethal epilepsy + raise the possibility that alteration in KCNH2-encoded K chan- (Fukata et al., 2010, Table 2). In the hippocampus, both Kv1.1 nels may confer susceptibility for epilepsy and cardiac LQT2 and Lgi1 appear co-assembled with Kv1.4 and Kvβ1inaxonal arrhythmia. terminals. In A-type channels composed of these subunits, Lgi1 prevents N-type inactivation mediated by the Kvβ1 subunit. In + AUXILIARY SUBUNITS OF K CHANNELS AND contrast, defective LGI1 molecules identified in ADLTE patients CHANNELEPSIES fail to exert this effect, which results in channels with rapid K+ channels expressed by distinct cell types may be formed by inactivation kinetics. These data suggest that these changes in unique hetero-oligomeric complexes comprising auxiliary sub- inactivation gating of presynaptic A-type channels may promote units. Several types of these subunits have been identified includ- epileptic activity (Schulte et al., 2006). ing beta-subunits (Kvβ), minK (minimal K+ channel peptide), Specific auto-antibodies underlie an emerging class of seizures MiRP (minK-related peptide), KChAP (K+ channel-associated named “autoimmune epilepsy” that involves K+ channels. protein), KChIP (K+ channel-interacting protein) and neuronal Indeed, several of these auto-antibodies do not bind directly with calcium sensor (NCS). Each type of auxiliary subunit modulates Kv1.1, Kv1.2, or Kv1.6 channels, as previously believed, but rather the activity of the associated K+ channel in distinct ways. Defects to associated proteins such as LGI1, contactin-associated protein in these subunits may alter the function of the channel and result 2(CASPR2), contactin-2, or others to be identified (Irani et al., in increased seizure susceptibility. 2010; Lai et al., 2010; Lancaster et al., 2011).

Kvβ CHANNELEPSY KvKChIP1 CHANNELEPSY Auxiliary subunits such as Kvβ1.1 and Kvβ1.2 confer fast N-type Cytosolic Kv channel-interacting proteins KChIP1–KChIP4 (An or A-type inactivation to non-inactivating Kv1 channels by means et al., 2000), which belong to the NCS family of calcium bind- of a “ball-and-chain” mechanism of pore occlusion whereby the ing EF-hand proteins, co-assemble with the N-terminus of Kv4 tethered (chain) positively charged inactivation particle (ball) subunits (Zhou et al., 2004) to form a native complex that in the amino-terminus of the Kvβ1 subunit binds to the intra- encodes major components of neuronal somatodendritic A-type + + cellular entrance of the pore discontinuing the outflow of K K current (IA). KChIP2 expression is high in the hippocam- ions. The fast inactivation of delayed-rectifier K+ channels is a pus, particularly within the apical dendrites of pyramidal cells. −/− physiologically relevant process, as it controls the firing prop- KChIP2 gene deletion in mice (Kchip2 )affectedtheIA in hip- erties of neurons and their response to input stimuli (Pessia, pocampus, namely reduced current density, decreased channel 2004). Surprisingly, Kvβ1.1 knockout mice do not display an availability, and slowed recovery from inactivation. This results overt epileptic phenotype. On the other hand, Kvβ2knockout in chronic hyper-excitability in hippocampal pyramidal neu- and Kvβ1/Kvβ2 double-knockout mice are characterized by an rons and Kchip2−/− mice exhibited increased susceptibility to increased neuronal excitability, occasional seizures, cold swim- seizures induced by kindling (Table 2). However, a compensatory induced tremors and a reduced life span (McCormack et al., up-regulation of inhibitory synaptic activity (up-regulation of 2002; Connor et al., 2005, Table 2). Clinical investigations have GABA currents) was also observed (Wang et al., 2013). These found an association between the severity of seizures, includ- findings indicated that KChIP2 is essential for homeostasis in ing infantile spasms and the loss of the Kvβ2 gene. Moreover, hippocampal neurons and mutations in these K+ channel aux- the hemizygosity of this gene in epileptic patients suggests that iliary subunits may be loci for epilepsy (Wang et al., 2013). haploinsufficiency for KCNAB2 is a significant risk factor for Interestingly, Kchip2−/− mice are highly susceptible to cardiac epilepsy (Heilstedt et al., 2001). Notably, Kvβ2 subunits do not arrhythmias (Kuo et al., 2001). Thus, this evidence suggests that confer fast inactivation properties to Kv1 channels, since they loss-of-function mutations in KChIP2 could confer an increased lack the inactivation particles. Thus, a chaperone-like function susceptibility to both seizures and cardiac arrhythmias, increasing has been proposed for these subunits. Although these findings the risk to sudden unexpected death in epileptic patients. are consistent with a role for accessory subunits in regulating In conclusion, these studies demonstrated that the auxiliary central nervous system excitability, further functional assays are subunits play important roles in the pathogenesis of epilepsy by

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affecting K+ channel function and network excitability in distinct 1996; Hu et al., 2001; Misonou et al., 2006; Martire et al., 2010). 2+ ways (see also KCa1.1 channelepsy). Inbrainneurons,theCa that activates KCa1.1 channels enters primarily through Cav channels (Berkefeld et al., 2006), with + CALCIUM-ACTIVATED K CHANNELS AND CHANNELEPSY which KCa1.1 channels strictly co-localize in order to be acti- + 2+ The calcium-activated K (KCa) channels are highly conserved vatedduringanactionpotentialbytheCa microdomains that 2+ across species, and widely expressed in the human brain. The phy- form around the Ca source (Müller et al., 2007). The KCa1.1 logenetic tree of the KCa channels shows that they are made of two channel activity is thus limited by the duration of the action + genetically well-distinct groups (Wei et al., 2005), the large con- potential-evoked Ca2 transients, and consequently restricted ductance (BK; KCa1.1), and the small/intermediate-conductance to the action potential repolarization phase and the fast por- (SK/IK; KCa2.1,KCa2.2,KCa2.3,KCa3.1)KCa channels. With regard tion of the after-hyperpolarization (fAHP; Sah and Faber, 2002), to gating mechanism, the Ca2+ sensitivity of SK/IK channels is and generally assumed to reduce neuronal excitability. Recent provided by tightly bound calmodulin (Xia et al., 1998; Fanger findings point, however, to a role of KCa1.1 channels in pro- et al., 1999), in contrast to the direct binding of Ca2+ at specific moting high frequency firing, an effect likely attributed to fast internal sites on the channel protein of KCa1.1 channels (Lee and spike repolarization, fAHP generation and the consequent reduc- Cui, 2010). Moreover, unlike the SK/IK channels, KCa1.1 channels tion in the activation of other slower Kv channels and of the + are also activated by voltage. inactivation of Na channels (Storm, 1987a,b; Gu et al., 2007). In brain neurons KCa channels are widely distributed in the Whereas they appear to be virtually uninfluential to synap- axons plasma membrane and at the presynaptic terminals (Knaus tic release modulation under physiologic conditions (Hu et al., et al., 1996; Blank et al., 2004), and often located close to voltage- 2001; Raffaelli et al., 2004; Shruti et al., 2008; Martire et al., 2+ gated Ca channels (Cav; Marrion and Tavalin, 1998). The 2010). 2+ Ca influx that follows neuronal excitation activates KCa chan- Given the role of KCa1.1 channels in promoting high neuronal nels whose outward K+ flux contributes to terminate the action firing frequency and their predominant expression in excitatory potential and establish the afterhyperpolarization (AHP) that neurons of cortex and hippocampus, it is no surprising that sev- closes Cav channels. This negative feedback control has been gen- eral lines of evidence from animal models point to a pro-epileptic erally assumed to make KCa channels critical players in opposing role for KCa1.1 channels. For example, spontaneous cortical burst- repetitive firing and hyperexcitability typical of epileptic disor- ing in mice with high susceptibility to convulsions was completely ders. To date only mutations in the KCa1.1 channel have been inhibited by the KCa1.1 channel blocker iberiotoxin (IbTX) (Jin clearly associated to epilepsy. et al., 2000). A similar inhibitory effect of KCa1.1 channel antago- nists was reported on chemoconvulsant-induced seizures in vitro KCa1.1 CHANNELEPSY and in vivo (Jin et al., 2000; Shruti et al., 2008; Sheehan et al., The KCa1.1 channel, originally cloned from the Drosophila slow- 2009). Finally, KCaβ4 knockout mice displayed temporal cortex poke , thus the name slo (Atkinson et al., 1991), is coded seizures and a gain-of-function of KCa1.1 channels in dentate gyrus by one single gene, the KCNMA1 (Wei et al., 2005). The vari- slices, resulting in higher firing rate (Brenner et al., 2005, Table 2). ety observed in biophysical and pharmacologic properties of Evidence for an association of human epilepsy with the KCa1.1 the channel derives from the extensive alternative splicing of its channel has also been found. A missense mutation (D434G) in the mRNA (Tseng-Crank et al., 1994), and the type of accessory KCNMA1 gene coding for the α subunit has been found in family β subunit (KCaβ) that associates with the channel (Jiang et al., patients suffering from generalized epilepsy and paroxysmal disk- 1999). The KCa1.1 channel is composed of four identical pore- inesia (Du et al., 2005, Table 1). Expression studies indicated that forming α subunits, each displaying a transmembrane portion the D434G mutant channel displayed markedly greater macro- very much like the Kv channel, with the voltage sensing domain scopic currents and single channel open probability, resulting made by segments S1–S4, and the permeating pore domain by the from a 5-fold increase in Ca2+ sensitivity (Du et al., 2005). In S5, P,and S6 segments. Unlike Kv channels, the KCa1.1 channel has accordance, the mutation appeared to be located in the RCK1 an additional transmembrane domain (S0), thought to subserve domain, close to the putative Ca2+ binding site and the segments 2+ for (KCaβ) subunit interaction and modulation of the channel subserving the allosteric coupling between Ca binding site and (Morrow et al., 2006). The channel has also a large C-terminal the activation gate (Yang et al., 2010). Subsequent studies showed 2+ cytosolic domain that confers Ca sensitivity to the channel. that the effects of the D434G mutation on the KCa1.1 channel Notably, the amino-acid sequence of the C-terminal domain con- properties were similar or even more pronounced in the pres- 2+ tains no conventional Ca binding motif such as EF hands or ence of the KCaβ1,KCaβ2,orKCaβ4 subunit, highly expressed in the C2 domains. The two putative high affinity Ca2+ binding sites of brain (Díez-Sampedro et al., 2006; Lee and Cui, 2009). Notably, a the channel are formed, respectively, by two closely located (five polymorphism in the KCaβ4 subunit has been associated to human amino acids apart) aspartate residues (Xia et al., 2002)onthe MTLE in an Irish cohort, but this has not been confirmed in other RCK1 (regulator of K+ conductance) domain, and by a series of populations (Cavalleri et al., 2007; Manna et al., 2013). By con- 2+ aspartate residues in a region known as the Ca bowl, located in trast, the α subunit coexpressed with KCaβ3b (a splicing variant of the RCK2 domain (Wei et al., 1994; Schreiber and Salkoff, 1997). KCaβ3) was modified by the mutation with a slowing of the acti- KCa1.1 channels expression predominates in axons and pre- vation, a reduction in the voltage-dependence, but no change in 2+ synaptic terminals of excitatory neurons located in epileptic rel- Ca -dependence, suggesting a loss-of-function of the KCa1.1 cur- evant structures, such as cortex and hippocampus (Knaus et al., rent (Lee and Cui, 2009). Interestingly, a KCaβ3 single-nucleotide

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mutation, causing a loss-of-function of KCa1.1 current containing they contribute to control neuronal excitability. In particular, the the KCaβ3b subunit, displays a small but significant association amplitude of Kir2.1 currents is small in young dentate gran- with idiopathic generalized epilepsy (Hu et al., 2003; Lorenz et al., ule neurons (DGCs), and increases ∼3-fold in mature DGCs to 2007, Table 1). Taken together, these data suggest that both a optimize their excitability. Thus, Kir2.1 channels play an impor- loss-of-function of KCaβ3b-containing KCa1.1 channels and a gain- tant role in DGCs firing properties during development (Mongiat of-function of KCaβ1,KCaβ2,orKCaβ4-containing KCa1.1 channels et al., 2009). Moreover, Kir2.1 channels in combination with would favor the epileptic phenotype, but more information on Kir4.1 control the astrocyte-mediated K+ buffering (Bordey and the location and function of KCaβ3b subunits is needed to clarify Sontheimer, 1998; Jabs et al., 2008; Chever et al., 2010). It has this point. been proposed that up-regulation of Kir2.1 in DGCs would coun- A modulation of KCa1.1 channel expression in epilepsy mod- terbalance the hyper-excitability observed in TLE, thus function- els has also been found. A gain-of-function of KCa1.1 cur- ingasananti-convulsant(Young et al., 2009). Individuals har- rents associated with increased spontaneous and evoked fir- boring loss-of-function mutations in KCNJ2 (e.g., Andersen-Tawil ing rates occurs in mouse neocortical pyramidal neurons 24 h syndrome; OMIM 170390) may present with mood disorders and after chemoconvulsant-induced generalized tonic-clonic seizures seizures (Haruna et al., 2007; Chan et al., 2010, Table 1), sug- (Shruti et al., 2008). Conversely, in a model of pilocarpine- gesting a possible role for Kir2.1 channels in the pathogenesis induced MTLE KCa1.1 channel α subunit was down-regulated at of neuropsychiatric disorders and epilepsy (Haruna et al., 2007; the protein and mRNA level in hyppocampal mossy fibers orig- Chan et al., 2010). inating from the dentate gyrus (Ermolinsky et al., 2008; Miceli et al., 2013). Notably, KCa1.1 channel proteins remaining after Kir3-GIRK-CHANNELEPSY seizure induction were mostly changed to the STREX splicing iso- Several neurotransmitters, including dopamine, opioid, somato- 2+ form, displaying an increased Ca -sensitivity with respect to the statin, acetylcholine, serotonin, adenosine, and GABA exert their ZERO splice variant normally present (Ermolinsky et al., 2008). actions by modulating the activity of G protein-coupled Kir The functional consequence of the observed changes is thus not channels (GIRK) belonging to the subfamily 3 (Kir3). Four sub- clear. units have been cloned: GIRK1-GIRK4, also known as Kir3.1– Kir3.4, that may heteropolimerize. Generally, receptors activation + INWARDLY-RECTIFYING K CHANNELS AND of intracellular heterotrimeric G proteins αβγ leads to stim- CHANNELEPSIES ulation of heteromeric Kir3 channels activity, resulting in an + Members of the inwardly-rectifying family of K channels (Kir) outward flux of K+ ions that causes membrane hyperpolariza- are found in virtually every cell type where they are major reg- tion and inhibition of cell excitability (Krapivinsky et al., 1995; + ulators of K fluxes across membranes (Hibino et al., 2010). Slesinger et al., 1995; Tucker et al., 1996a). The crystal structure The principal role of most Kir channels is the maintenance of of this channel type has been resolved, recently (Whorton and the resting membrane potential and thereby the control of cell Mackinnon, 2013). Gain-of-function of Kir3 channels can con- excitability, while others subserve the transport and recycling of siderably reduce neuronal activity, whereas loss-of-function can + + K across membranes. Like other K channels, Kir subunits lead to excessive neuronal excitability and epilepsy. Indeed, abla- assemble as tetramers, and their ability to heteromultimerise adds tion of the gene encoding for Kir3.2 channels (GIRK2) results in functional diversity to a limited number of gene products. Kir spontaneous convulsions and increased susceptibility for gener- subunits possess two transmembrane domains and approximately alized seizures in rodents (Signorini et al., 1997, Table 2). The 15 distinct Kir clones have been identified so far, forming seven principal phenotype of weaver mice (wv/wv) is an ataxic gait, major subfamilies: Kir1–Kir7 (Bond et al., 1994; Hibino et al., due to severe hypoplasia of the cerebellum, learning deficits 2010). Important physiological roles have been established for and epileptic seizures. Weaver mice carry a deleterious muta- nearly all of these subfamilies. Generally, a Kir channel acts as tion in the pore of Kir3.2 channels (G156S; Patil et al., 1995, a diode whereby the inward current through these channels is Table 2). This mutation alters the K+ selectivity of the channel, greater at potentials more negative than the EK,ascomparedto induces calcium overload in cells, and reduces channel availabil- more positive values, where the outward flow is inhibited and the ity (Slesinger et al., 1996; Tucker et al., 1996b) with a mech- membrane potential free to change. The rectifying nature of Kir anism different from heteromeric subunit degradation (Tucker channels is due to a voltage-dependent block of the intracellu- et al., 1996c). It is likely that these molecular defects, induced + lar side of the pore by cytoplasmic polyamines and Mg2 ions by the G156S mutation, would lead to neurodegeneration and (Matsuda et al., 1987; Lopatin et al., 1994; Lu and MacKinnon, seizures susceptibility that characterize the phenotype of weaver 1994; Stanfield et al., 1994). Several studies highlighted the role of mice. + inwardly-rectifying K channels’ dysfunction in neuropsychiatric Kir3 channel inhibition, induced by intrathecal adminis- disorders and epilepsy although the relevant mechanisms in some tration of tertiapin, is pro-convulsant (Mazarati et al., 2006). instances await clarification. Moreover, several drugs used in clinics—desimipramine, flu- oxetine, haloperidol, thioridazine, pimozide and clozapine— Kir2 CHANNELEPSY inhibit Kir3 channel activity, and cause seizures as side effect. Kir2.1 channels are highly expressed in brain, particularly in hip- Conversely, electroconvulsive shock leads to increased expression pocampus, caudate, putamen, nucleus accumbens, and to lower of Kir3 channels (Pei et al., 1999), which may provide compen- levels in habenula and amygdala (Karschin et al., 1996), where satory mechanisms against excessive electrical activity leading to

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neuroprotection. In support of this hypothesis, stimulation of and potassium clearance (Jauch et al., 2002). Moreover, loss- galanin type 2 receptors that activate GIRK channels prevents of-function recessive mutations of KCNJ10 (Kir4.1) have been kindled epileptogenesis in rats (Mazarati et al., 2006). In con- recently associated with a disease, named EAST syndrome or clusion, these studies point out that distinct changes in Kir3 SeSAME syndrome, consisting of seizures, ataxia, sensorineural channel activity or availability throughout the brain may result deafness, mental retardation, and renal salt-losing tubulopathy in pro-convulsant or anti-convulsant effects. (Bockenhauer et al., 2009; Scholl et al., 2009, Table 1). A number of additional elements substantiate the hypothesis that variants Kir4/Kir5 CHANNELEPSY in KCNJ10 might contribute to brain dysfunction and seizures Kir4.1 subunits (KCNJ10; BIR10; Bond et al., 1994; Lagrutta et al., susceptibility. Conditional knockout mice lacking Kir4.1 exhibit 1996) may form homomeric channels or may polymerize with stress-induced seizures, severe ataxia, spongiform vacuolation, Kir5.1 (KCNJ16) to form heterotetramers (Pessia et al., 1996) axonal swellings, and degeneration, in addition to loss highly sensitive to pH (Tucker et al., 2000; Pessia et al., 2001; and premature lethality (Neusch et al., 2001; Djukic et al., 2007, Casamassima et al., 2003; D’Adamo et al., 2011b). Kir4.1 chan- Table 2). In Kir4.1 knockout glial cells, no variations in mem- + nels are expressed primarily in oligodendrocytes and astrocytes brane potential were observed during increases in [K ]o induced surrounding synapses and blood vessels, mainly in the cortex, by nerve stimulations (Chever et al., 2010). Hence, it has been thalamus, hippocampus, and brainstem (Takumi et al., 1995; proposed that the loss-of-function of glial K+ conductance would Higashi et al., 2001). Kir4.1 channel activity shows a profound favor extracellular K+ accumulation, contributing to neuronal developmental regulation, which correlates with both cell differ- hyperexcitability and epilepsy (Orkand et al., 1966; Chever et al., entiation and the developmental regulation of extracellular K+ 2010). dynamics (Connors et al., 1982; MacFarlane and Sontheimer, Epilepsy and autism spectrum disorders (ASD) are strongly 2000; Neusch et al., 2001). Kir4.1 controls primarily the resting associated. The prevalence of seizures is highly represented in membrane potential of astrocytes, and maintains the extracellular ASD (5–46%) (Bryson et al., 1988; Hughes and Melyn, 2005), ionic and osmotic environment by promoting K+ transport from compared with the general population (0.5–1%). The prevalence + regions of high [K ]o, which results from synaptic excitation, to of autism in the epilepsy population is ∼32%, which is about 50 + + those of low [K ]o. This polarized transport of K in astrocytes, times higher than in the general population (Clarke et al., 2005). referred to as “spatial buffering of K+” is essential for normal An “autism–epilepsy phenotype” has been identified (Tuchman neuronal activity, excitability, and synaptic functions. Among et al., 2009). Recently we reported a mutational screening of the genes associated with different forms of epilepsy Kir4.1 is KCNJ10 in 52 children with cryptogenic epilepsy that resulted receiving increasing interest. Genetic studies have indicated a in the identification of two heterozygous KCNJ10 mutations in linkage between missense variations in Kir4.1 and seizure suscep- two identical twins (R18Q) and in a 14-year-old child (V84M; tibility (Buono et al., 2004; Connors et al., 2004, Table 1). The Sicca et al., 2011, Table 1). Clinically, the two 8-year-old iden- DBA/2 mouse strain exhibits a greater susceptibility to induced tical twins showed impaired social interaction, sleep difficulties, seizures compared to the C57BL/6 strain. Previous QTL map- hypotonia and both exhibited epileptic spasms within the same ping identified the seizure susceptibility locus (Szs1) on the distal 24 h period. Other symptoms, typical of ASD, included clum- region of mouse 1 and further fine mapping stud- siness, absence of speech, severe disorder of social interaction, ies suggested that a missense variation (T262S) in Kcnj10 was the stereotypies, repetitive behaviors, symptoms of anxiety, depres- likely candidate for this linkage (Ferraro et al., 2004, Table 2). sion, obsessive compulsive disorder and intellectual disability (IQ: Inasecondlinkagestudy,avariationinthehumanKCNJ10 58). The 14-year-old child showed normal psychomotor devel- gene (R271C) was associated with seizure resistance in groups of opment until 12 months of age, when ASD symptoms such as patients with either focal or generalized epilepsy (Buono et al., poor social gaze, no response to name, absence of language devel- 2004). However, a functional study demonstrated that these vari- opment, and withdrawal behaviors became evident. At the age ations (T262S and R271C) do not produce any observable change of 6, he experienced complex partial seizures. EEG recordings in channel function or in predicted channel structure (Shang showed synchronous and asynchronous paroxysmal abnormali- et al., 2005). It is therefore unlikely that the seizure suscepti- ties over frontal regions in both hemispheres tending to spread. bility phenotypes associated with these missense variations are The functional consequences of these heterozygous mutations caused by changes in the intrinsic functional properties of Kir4.1. were gain-of-function of either Kir4.1 or Kir4.1/Kir5.1 channels However, this study was unable to comprehensively disprove this (Sicca et al., 2011). To date, we have identified several new association, and alterations in Kir4.1 channel activity remain an probands displaying an autism–epilepsy phenotype who carry attractive mechanistic hypothesis. Future investigations willing mutations in KCNJ10 that cause gain-of-function effects, assessed to prove the association between these variants and seizure sus- by using astrocytoma cell lines. Collectively, our findings point ceptibility phenotypes should include examination of how these to a new class of genes that should be examined in autism- variants could produce subtle changes in their interaction with epilepsy patients, and disclose novel molecular mechanisms that cell-specific trafficking or regulatory proteins, or other possible may increase the susceptibility to this distinct neuropsychiatric pathways. phenotype by altering the K+ homeostasis in the brain (D’Adamo Recordings from surgical specimens of patients with et al., 2011a; Sicca et al., 2011). Indeed, Kir4.1 is the main glial intractable epilepsies have demonstrated a reduction of Kir inward conductance, astrocytes make up 90% of all human brain conductance in astrocytes (Bordey and Sontheimer, 1998) cells, and each astrocyte controls the activity of many thousands

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of synapses (about 140,000 in the hippocampus; Benarroch, systems or enhance the activatory effects of Mg2+-nucleotides. 2009). Co-occurrence of epilepsy and ASD in patients harboring This reduction in ATP sensitivity translates in more fully open- KCNJ10 gain-of-function mutations suggests that dysfunction in ings of the channel at physiologically relevant concentrations + the astrocytic-dependent K buffering may be a common mech- of ATP, increased KATP current, hyperpolarization of the β-cell anismcontributingtoseizuresaswellasthecorebehavioral plasma membrane, and consequent suppression of Ca2+ influx features of ASD. It has been shown that an isolated episode of local andinsulinsecretion(Hattersley and Ashcroft, 2005). Clinical + neuronal hyperactivity triggers a large and synchronous Ca2 severity of the disorder correlates with the magnitude of shift elevation in closely associated astrocytes. Activated astrocytes in the ATP affinity. Sulfonylureas, which block opened chan- signal back to neurons favoring their recruitment into a coher- nels and restore glucose homeostasis, ameliorate some of the ent activity that underlines the hypersynchronous ictal discharge neurological symptoms of DEND syndrome. How KATP channel (Gómez-Gonzalo et al., 2010). It is possible that an increased over-activity in the central nervous system results in epilepsy is + and faster influx of K into astrocytes through high function- unclear. Whereas insights have been provided on the mechanisms ing Kir4.1-containing channels may lead, during intense neuronal linking loss of KATP channel function to increased seizure suscep- activity, to larger membrane depolarization and higher intracellu- tibility. Notably, generalized seizures can be evoked by metabolic + + lar Ca2 elevations in these cells. Ca2 elevations in astrocytes are stresses such as hypoxia and hypoglycemia. Kir6.2 knockout mice associated with the release of gliotransmitters, such as glutamate exhibited high-voltage sharp-wave bursts in the EEG recordings, and D-serine, which trigger discharges in neurons, promote local myoclonic jerks followed by severe tonic-clonic convulsion and neuronal synchrony and epileptic activity (Parpura et al., 1994; death upon exposure to hypoxia (Table 2). However, the wild- Bezzi et al., 1998; Pasti et al., 2001; Angulo et al., 2004; Fellin et al., type mice remained sedated during this challenge and revived 2004; Mothet et al., 2005; Tian et al., 2005). Speculatively, a recur- normally (Yamada et al., 2001). Substantia nigra pars reticulata rent neuron-astrocyte-neuron excitatory loop may develop at a (SNr) and its efferents act as a central gating system in the prop- restricted brain site, as a consequence of gain-of-function of Kir4.1 agation of seizure activity (Iadarola and Gale, 1982). Remarkably, channels, and contribute to initiation of seizures. These muta- wild-type neurons in brain slices from the substantia nigra pars tions may alter the noradrenergic (NA) system of the brain as reticulata (SNr) were hyperpolarized by hypoxia, whereas the well, since Kir4.1/Kir5.1 channels control the excitability of locus membrane potential of Kir6.2 knockout neurons were depolar- coeruleus (LC) neurons (D’Adamo et al., 2011b). Indeed, a devel- ized by the perfusion with hypoxic solutions. The SNr and its opmental dysregulation of this LC-NA network (Samuels and efferents act as a central gating system in the propagation of Szabadi, 2008) has been suggested to underlie epilepsy. From a seizure activity (Iadarola and Gale, 1982). Therefore, hyperpolar- therapeutic perspective, these studies indicate that, alike neurons, ization of SNr neurons upon opening of KATP channels has been astrocytes may represent a crucial target for the pharmacological proposed to protect against seizure propagation during metabolic control of abnormal electrical discharge and synaptic function. stress, although other brain regions could be involved in this process (Yamada et al., 2001). Kir6-KATP -CHANNELEPSY + The adenosine triphosphate (ATP)-sensitive K (KATP ) channels CONCLUDING REMARKS are octamers composed of four pore-forming subunits, consist- Solving the puzzle of epilepsy is an extremely difficult task. ing of Kir6.1 or Kir6.2, with four regulatory sulfonylurea receptors Here we have put several new pieces in the puzzle by describ- such as SUR1, SUR2A, or SUR2B, which are members of the ATP- ing novel genetic defects in K+ channels and related pro- binding-cassette transporter family (Aguilar-Bryan et al., 1995; teins that underlie distinct human epileptic phenotypes. We Inagaki et al., 1995; Nichols et al., 1996). The secretion of insulin have also analyzed critically the new insights in the neuro- from pancreatic β-cells is mediated by the closure of these chan- biology of this disease that have been provided by investiga- nels caused by increased levels of cytoplasmic ATP. Neuronal tions on valuable animal models of epilepsy. It is becoming + KATP channels are predominantly composed of Kir6.2/SUR1, increasingly clear that mutations in K channel genes or per- although Kir6.1/SUR2B and Kir6.2/SUR2B are also found. These turbations in K+ channel function, even in the absence of channels link the metabolic state of neurons to their excitabil- a primary channel defect, underlie an increased susceptibility ity by sensing changes in intracellular phosphate potential (i.e., to epilepsy. Despite the abundance of genes encoding for K+ ATP/ADP ratio). DEND syndrome (OMIM 606176) is an inher- channels and associated subunits, and their established crucial ited disease characterized by developmental delay, epilepsy and functional roles, these genes have been greatly overlooked in neonatal diabetes mellitus. Twenty percent of these patients have the search for the causes underlying idiopathic epilepsy. The associated neurologic defects, the most severe of which are gener- extremely high diversity of K+ channels and the numerous muta- alized epilepsy, marked delay of motor and social development, tions identified in their genes often generate confusion in the including late development of speech, and learning difficulties. classification of the associated diseases. Therefore, we proposed Numerous gain-of-function mutations have been identified in the to name the K+ channels defects underlying distinct epilep- genes encoding Kir6.2 (KCNJ11) or the associated regulatory sies as “K+ channelepsies” and suggested a new classification SUR1 subunit (ABCC8) of patients affected by DEND syndrome according to a widely used K+ channel nomenclature (Chandy (Table 1). To date, all mutations in KCNJ11 that have been char- and Gutman, 1993; Kubo et al., 2005; Wei et al., 2005). This acterizedfunctionally,producemarkeddecreaseintheabilityof original classification could be also adopted to easily unify, ATP to inhibit the KATP channel when expressed in heterologous identify and describe multiple organ dysfunction related to a

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single gene defect (e.g., Kx.y-phenotype; Navx.y- pathways and circuits involved in epilepsy. The understanding + phenotype;Cavx.y-phenotype)(Catterall et al., 2005a,b). K of these “experiments” of Nature will also help us to uncover, channels represent crucial targets for novel pharmacological in a much broader sense, the physiological workings of the control of abnormal electrical discharges and synaptic func- human body. tion in the brain. Much greater efforts should thus be made to find new K+ channel modulators and gene therapies to ame- ACKNOWLEDGMENTS liorate the symptoms of this devastating disease. On the other This work was supported by Telethon (GGP11188), hand, the effects of newly developed drugs on the activity of Ministero della Salute (GR-2009-1580433); MIUR-PRIN most K+ channel types should be tested in order to predict 20108WT59Y_004; COMPAGNIA di San Paolo (Turin) their pro-convulsant side effects. Research on K+ channelep- “Programma Neuroscienze,” and Fondazione Cassa di Risparmio sies is clearly providing important knowledge on the signaling di Perugia.

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The auxiliary of inward rectifier K+ (Kir2) chan- the Creative Commons Attribution rat brain and down-regulation subunit KChIP2 is an essential reg- nels in dentate gyrus granule cells License (CC BY). The use, distribution in the hippocampus following ulator of homeostatic excitability. in temporal lobe epilepsy. J. Physiol. or reproduction in other forums is per- seizures. Neuron 8, 1055–1067. doi: J. Biol. Chem. 288, 13258–13268. 587, 4213–4233. doi: 10.1113/jphys- mitted, provided the original author(s) 10.1016/0896-6273(92)90127-Y doi: 10.1074/jbc.M112.434548 iol.2009.170746 or licensor are credited and that the Tseng-Crank, J., Foster, C. D., Krause, Wang, Q., Curran, M. E., Splawski, Zahn,R.K.,Tolner,E.A.,Derst, original publication in this journal J.D.,Mertz,R.,Godinot,N., I., Burn, T. C., Millholland, J. C.,Gruber,C.,Veh,R.W., is cited, in accordance with accepted DiChiara, T. J., et al. (1994). Cloning M., VanRaay, T. J., et al. (1996). and Heinemann, U. (2008). academic practice. No use, distribution expression and distribution of func- Positional cloning of a novel Reduced ictogenic potential of 4- or reproduction is permitted which does tionally distinct Ca2+-activated potassium channel gene: KVLQT1 aminopyridine in the perirhinal and not comply with these terms.

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