Progress in brain research, volume 213

Advisory Editors Stephen G Waxman Bridget Marie Flaherty Professor of Neurology Neurobiology, and Pharmacology; Director, Center for Neuroscience & Regeneration/Neurorehabilitation Research Yale University School of Medicine New Haven, Connecticut USA Donald G Stein Asa G Candler Professor Department of Emergency Medicine Emory University Atlanta, Georgia USA Dick F Swaab Professor of Neurobiology Medical Faculty, University of Amsterdam; Leader Research team Neuropsychiatric Disorders Netherlands Institute for Neuroscience Amsterdam The Netherlands Howard L Fields Professor of Neurology Endowed Chair in Pharmacology of Addiction Director, Wheeler Center for the Neurobiology of Addiction University of California San Francisco, California USA Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands The Boulevard, Langford Lane, Kidlington, Oxford, OX5 1GB, UK First edition 2014 Copyright # 2014 Elsevier B.V All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-444-63326-2 ISSN: 0079-6123 For information on all Elsevier publications visit our website at store.elsevier.com Printed and bound in Great Britain Contributors Ste´phanie Baulac Sorbonne Universite´s, UPMC Univ Paris 06, UM 75; INSERM, U1127; CNRS, UMR 7225, and Institut du Cerveau et de la Moelle e´pinie`re, ICM, Paris, France Ingmar Bluămcke Department of Neuropathology, University Hospital Erlangen, Schwabachanlage, Erlangen, Germany John K Cowell Georgia Regents University Cancer Center, Augusta, GA, USA Laura Flores-Sarnat Department of Paediatrics, and Department of Clinical Neurosciences, Faculty of Medicine and Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada Antonio Gambardella Institute of Neurology, Department of Medical Sciences, University Magna Graecia, Catanzaro, Italy David A Greenberg Battelle Center for Mathematical Medicine, Nationwide Children’s Hospital and Pediatrics Department, Wexner Medical Center, Ohio State University, Columbus, OH, USA Ingo Helbig Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, USA Shinichi Hirose Department of Pediatrics, School of Medicine, and Central Research Institute for the Molecular Pathomechanisms of Epilepsy, Fukuoka University, Fukuoka, Japan Katja Kobow Department of Neuropathology, University Hospital Erlangen, Schwabachanlage, Erlangen, Germany Angelo Labate Institute of Neurology, Department of Medical Sciences, University Magna Graecia, Catanzaro, Italy Holger Lerche Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuăbingen, Tuăbingen, Germany Atul Maheshwari Department of Neurology, Developmental Neurogenetics Laboratory, Baylor College of Medicine Houston, TX, USA v vi Contributors Snezana Maljevic Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuăbingen, Tuăbingen, Germany Berge A Minassian Division of Neurology, Department of Paediatrics; Program in Genetics and Genome Biology, The Hospital for Sick Children, and Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada Carlo Nobile CNR-Neuroscience Institute, Section of Padua, Viale G, Colombo, Padova, Italy Jeffrey L Noebels Department of Neurology, Developmental Neurogenetics Laboratory; Department of Neuroscience, and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA Harvey B Sarnat Department of Paediatrics; Department of Pathology (Neuropathology), and Department of Clinical Neurosciences, Faculty of Medicine and Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada Ortrud K Steinlein Institute of Human Genetics, University Hospital, Ludwig-Maximilians-University, Munich, Germany William L Stewart Battelle Center for Mathematical Medicine, Nationwide Children’s Hospital and Pediatrics Department, Wexner Medical Center, Ohio State University, Columbus, OH, USA Pasquale Striano Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, “G Gaslini” Institute, Genova, Italy Preface There has never been a time before in the history of epilepsy research when scientists reached such a high level of knowledge The amazing amount of data collected within the last two decades greatly facilitated our understanding of basic concepts of epileptogenesis On the other hand, this progress came with the insight that the mechanisms underlying seizure generation are far more complex than previously thought Twenty years ago, the introduction of the concept of epilepsies as channelopathies seemed to offer a plausible pathogenetic concept Since then, it has become obvious that ion channels are only part of the story, and that even a bona fide mutation within an ion channel cannot be taken as a proof that disturbed channel function directly translates into neuronal hyperexcitability More complex mechanisms have to be considered, and some of them might even precede the first clinically visible seizure by many years or even decades It also has become obvious that a, most likely large, number of genes exist that are directly associated with symptomatic or genetic epilepsies but are neither coding for an ion channel subunit nor for a protein that has any detectable interactions with such an ion channel Apparently, new pathogenetic concepts are needed to guide researchers through the ever-increasing complexity of a field that less than half a century ago had still been dominated by the hypothesis that a single “epilepsy gene” exists Nowadays, it is clear that a large number of epilepsy genes hide in our genome, and that these genes are able to cause seizures by many different mechanisms, both directly and indirectly The selection of topics presented by the chapters in this book reflects this pathogenetic heterogeneity as far as this is even possible in a single volume These chapters are not aiming to simply present a summary of facts but rather try to offer the reader a broad view of the scientific concepts, theories, and approaches that presently dominate the different fields in epilepsy research The group of authors that contributed to this book is as heterogeneous as the epilepsies themselves, including geneticists, electrophysiologists, and clinical researchers This makes for a lively and sometimes refreshingly controversial discussion, providing the readers with a wealth of different views, hypotheses, and ideas that hopefully create a fertile ground for the development of successful future research strategies Ortrud K Steinlein vii CHAPTER Genetic heterogeneity in familial nocturnal frontal lobe epilepsy Ortrud K Steinlein1 Institute of Human Genetics, University Hospital, Ludwig-Maximilians-University, Munich, Germany Corresponding author: Tel.: (+49)89-5160-4468; Fax: (+49)89-5160-4470, e-mail address: ortrud.steinlein@med.uni-muenchen.de Abstract Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was the first epilepsy in humans that could be linked to specific mutations It had been initially described as a channelopathy due to the fact that for nearly two decades mutations were exclusively found in subunits of the nicotinic acetylcholine receptor However, newer findings demonstrate that the molecular pathology of ADNFLE is much more complex insofar as this rare epilepsy can also be caused by genes coding for non-ion channel proteins It is becoming obvious that the different subtypes of focal epilepsies are not strictly genetically separate entities but that mutations within the same gene might cause a clinical spectrum of different types of focal epilepsies Keywords ADNFLE, nocturnal frontal lobe epilepsy, epileptic encephalopathy, acetylcholine receptor, KCNT1, DEPDC5 INTRODUCTION Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was first described as a distinct familial partial epilepsy in 1994 (Scheffer et al., 1995) Although rare, it is often referred to not least because of its status as the very first idiopathic epilepsy in humans for which the underlying genetic cause had been identified (Steinlein et al., 1995) This was achieved at a time when molecular genetics was still a rather new field, 300,000-marker genome-wide association studies unheard of, and highthroughput sequencing a vision rather than daily routine Genotyping of only about 200 polymorphic markers led to the identification of a strong candidate locus for ADNFLE on the tip of the long arm of chromosome 20 in a large Australian family Progress in Brain Research, Volume 213, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63326-2.00001-6 © 2014 Elsevier B.V All rights reserved CHAPTER Genetic heterogeneity that included more than 25 affected individuals (Phillips et al., 1995) At that time, this chromosomal region was already in the process of being characterized due to the fact that some years previously it had been identified as a candidate region for another type of rare monogenic idiopathic epilepsy, named benign familial neonatal convulsions (BFNCs) (Leppert et al., 1989) It turned out that the region on chromosome 20q contains two different ion channel subunit genes, CHRNA4 encoding the a4-subunit of the neuronal nicotinic acetylcholine receptor and the voltage-gated potassium channel gene KCNQ2 (Steinlein et al., 1994) The latter one was proven to be the major gene for BFNC, while CHRNA4 (and some years later CHRNB2) was identified as one of the main genes that cause ADNFLE (Biervert et al., 1998; De Fusco et al., 2000; Singh et al., 1998; Steinlein et al., 1995) The identification of these first two seizure-related genes introduced the concept of epilepsies as channelopathies, a concept that has by now gotten firmly established by the discovery of several additional epilepsy-causing ion channel genes Today, nearly 20 years later, ADNFLE is again attracting attention by teaching us that one and the same disorder can be both a channelopathy and a non-ion channel disorder (Dibbens et al., 2013; Ishida et al., 2013; Ishii et al., 2013; Martin et al., 2013) (Fig 1; Table 1) CHRNA4 AND CHRNB2: THE “CLASSICAL” ADNFLE GENES The nAChR subunit genes CHRNA4 and CHRNB2 are responsible for the clinical phenotype in about 12–15% of ADNFLE patients with a strong family history (Steinlein et al., 2012) Both genes are expressed throughout the brain and the proteins they encode ensemble to build one of the most widely expressed nAChRs (3a4/2b2 or 2a4/3b2) in mammalian brain The ubiquitous expression pattern of this nAChR subtype is surprising given that mutations in these genes cause a seizure KCNT1 CHRNA4 E L F N D A CHRNB2 DEPDC5 CHRNA2 DEPDC5 KCNT1 Frontal lobe Parietal lobe Temporal lobe Occipital lobe DEPDC5 DEPDC5 FIGURE Schematic overview summarizing the seizure origin of the known ADNFLE genes Arrows indicate the migrating seizures reported for several patients with KCNT1 mutations CHRNA4 and CHRNB2: The “classical” ADNFLE genes Table Clinical phenotypes associated with ADNFLE genes Genes Function Clinical phenotypes CHRNA4/ CHRNB2 CHRNA2 KCNT1 Ion channel ADNFLE Ion channel Ion channel (signaling function?) DEPDC5 Non-ion channel NFLE (ADNFLE?) Malignant migrating partial seizures Early infantile epileptic encephalopathy Severe ADNFLE Focal epilepsy with variable foci ADNFLE The question mark indicates that the clinical phenotype overlaps with that previously described in other ADNFLE families but might not be identical phenotype that originates from the frontal lobe and rarely shows secondary generalization So far, it can only be speculated about the pathomechanisms that prevent CHRNA4 and CHRNB2 mutations from having a more widespread effect A possible explanation for this phenomenon could be that in most parts of the brain the effect the mutations have on neuronal excitability can be compensated by other nAChR subunits Another possibility would be that genes from other ion channel families or even non-ion channel genes are involved in this restricted seizure activity So far, nearly all of the ADNFLE mutations identified within CHRNA4 or CHRNB2 are missense mutations that cause amino acid exchanges within the second, less often the first, transmembrane domain (Bertrand et al., 2005; Cho et al., 2003; De Fusco et al., 2000; Hirose et al., 1999; Magnusson et al., 2003; Phillips et al., 1995; Steinlein et al., 1995) The nAChR genes encode receptor subunits with four transmembrane domains These are either directly or indirectly contributing to the structure that forms the walls of the ion channel and to the governing of the channels opening and closing mechanism The second transmembrane domain, consisting of helical segments forming an inner ring (TM2) that shapes the pore, can be regarded as a hot spot for ADNFLE mutations Several of these mutations have been identified more than once in unrelated families from different countries or even continents This includes the neighboring mutations CHRNA4-Ser280Phe and CHRNA4Ser284Leu that are so far the most commonly detected ADNFLE mutations (Cho et al., 2003; Hirose et al., 1999; Ito et al., 2000; McLellan et al., 2003; Phillips et al., 2000; Rozycka et al., 2003; Steinlein et al., 1995, 2000) These two mutations are only separated by a few amino acids, but nevertheless differ markedly with respect to both their biopharmacological characteristics and the severity of the clinical phenotype they are associated with Most of the patients carrying CHRNA4Ser280Phe present with an “epilepsy-only” phenotype, while many of those with CHRNA4-Ser284Leu have additional neurological symptoms such as mildto-moderate mental retardation Furthermore, the latter group of patients tend to have an unusually early age of onset, while carriers of the CHRNA4-Ser280Phe mutation CHAPTER Genetic heterogeneity develop their seizures at an average age that is typical for most nAChR-caused nocturnal frontal lobe epilepsies (Bertrand et al., 2002; Cho et al., 2003; Hirose et al., 1999; Ito et al., 2000; McLellan et al., 2003; Phillips et al., 2000; Rozycka et al., 2003; Steinlein et al., 1995, 2000) On a molecular level, the two mutations differed significantly with respect to their carbamazepine sensitivity, an antiepileptic drug that in vivo was shown to be highly effective on CHRNA4-Ser280Phe carrying nAChRs but not on those with the mutation CHRNA4-Ser284Leu (Bertrand et al., 2002) These results, gained from the analysis of nAChRs expressed in Xenopus oocytes, fit in with the observation that patients with the mutation CHRNA4Ser280Phe usually benefit from carbamazepine treatment, while sufficient seizure reduction is rarely achieved by carbamazepine monotherapy in patients carrying CHRNA4-Ser284Leu (Bertrand et al., 2002; Cho et al., 2003; Hirose et al., 1999; Ito et al., 2000; McLellan et al., 2003; Phillips et al., 2000; Rozycka et al., 2003; Steinlein et al., 1995, 2000) THE CLINICAL SPECTRUM OF nAChR-CAUSED ADNFLE The term nocturnal frontal lobe epilepsy describes a large group of partial epilepsies that are heterogeneous in origin ADNFLE as a rare monogenic disorder only accounts for a small proportion of these epilepsies that are mostly either symptomatic or multifactorial Patients with sporadic as well as familial nocturnal frontal lobe epilepsy mostly show hypermotoric seizures with movements and vocalizations Due to their often bizarre nature, the seizures might be misdiagnosed, for example, as a kind of nonepileptic movement disorder, night terrors, or pseudoseizures Electroencephalograms (EEGs) are not always helpful to establish the diagnosis because, as commonly found in frontal lobe epilepsies, they tend to be normal both interictally and ictal Consciousness is usually not impaired during seizures and postictal confusion is not observed Diurnal seizures might happen; however, most of these seizures occur during daytime naps, while seizures during wakefulness are a rare and infrequent event (Scheffer et al., 1995; Vigevano and Fusco, 1993) Seizure onset most often happens during the second decade of life; however, it can vary considerably even within the same family (mean age of onset is 14 years (14 Ỉ 10 years)) In many individuals, seizures become milder and less frequent once they reach middle age A possible explanation for this phenomenon could be the normally occurring subtle decline in the number of expressed nAChRs with age The very first reports described ADNFLE as a rather benign type of epilepsy that affects otherwise healthy individuals and is readily controlled by carbamazepine However, follow-up reports put a question mark behind this initial assessment This was mainly due to the frequency with which additional major neurological symptoms were found in patients affected by this “benign” epilepsy A considerable degree of interindividual variation is observed with respect to the neuropsychological development of the patients It can range from normal intelligence to selected cognitive deficits to different degrees of mental retardation Cognitive impairment seems to be CHRNA2: A rare cause of familial NFLE frequently associated with certain ADNFLE mutations while being rather rare with other mutations (Bertrand et al., 2005; Hirose et al., 1999; Steinlein et al., 2012) The same applies to psychiatric symptoms such as schizophrenia-like psychosis that was present in most patients from a Norwegian ADNFLE family but is not usually seen in other patients with the same disorder (Magnusson et al., 2003) The results of a metaanalysis including 19 families with 10 different mutations in either CHRNA4 or CHRNB2 suggest that some of these mutations are frequently associated not only with epilepsy but also with additional major cognitive or psychiatric symptoms, while other ADNFLE mutations are preferentially found in “epilepsy-only” families Another feature in which patients with ADNFLE demonstrate considerable interindividual variability is the sensitivity with which their seizures respond to antiepileptic drug treatment In many families, especially those with mutations such as CHRNA4-Ser280Phe (previous name Ser248Phe), seizures are sufficiently controlled by the antiepileptic drug carbamazepine Seizures in patients with other ADNFLE mutations (for example, CHRNA4-Ser284Leu or CHRNA4-Thr293Ile (previously named Ser252Leu or Thr265Ile)) not respond easily to carbamazepine or other antiepileptic drugs and might require a multidrug treatment strategy Quite often, the latter type of ADNFLE mutation is associated with an increased risk for major comorbidities such as mental retardation or psychiatric symptoms (Cho et al., 2003; Hirose et al., 1999; Steinlein et al., 1995) The reservation must be made, however, that for most nAChR mutations the number of known ADNFLE families is still too small to derive reliable genotype–phenotype relations from them CHRNA2: A RARE CAUSE OF FAMILIAL NFLE So far, only a single mutation (Ile279Asn) has been described in CHRNA2, a gene that encodes one of the major a-subunits of the nAChR (Aridon et al., 2006; Combi et al., 2009; Gu et al., 2007) The mutation was found in a family of Italian origin in which 10 members were affected by nocturnal epilepsy The seizure phenotype was characterized by arousal from sleep, followed by prominent fear sensation and tongue movements Compared to other ADNFLE families, a rather high rate of nocturnal wanderings was reported It is therefore not entirely clear yet if the phenotype in this family is indeed ADNFLE or if is better classified as a separate entity of nocturnal frontal lobe epilepsy (Hoda et al., 2009) Analyses of CHRNA2-Ile279Asn on a molecular basis showed that expression of nAChRs carrying this mutation in Xenopus oocytes significantly increases the number of receptors expressed at the membrane surface The mutated receptors also yielded higher ACh-evoked currents and showed a markedly increased sensitivity toward their natural agonist acetylcholine Taken together, it can be concluded that, comparable to the impact ADNFLE mutations within the CHRNA4 and CHRNB2 genes have, the CHRNA2 mutation results in a gain-of-function effect, at least in the 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Bernstein, B.E., Lengauer, T., Gnirke, A., Meissner, A., 2011 Genomic distribution and inter-sample variation of non-CpG methylation across human cell types PLoS Genet 7, e1002389 Index Note: Page numbers followed by f indicate figures and t indicate tables A Absence epilepsy AMPA receptors, 236–237 cortex and thalamus, 224 description, 224 developmental stage, 224–225 drug treatment, 243 EEG recordings, 228 feedforward inhibition (see Feedforward inhibition, absence epilepsy) GABAA receptors, 235f, 237–238 genetic mutations, mice, 225, 226t human CAE genes, 228, 229t mechanisms, 224–225 P/Q-type calcium channels, 233–236 sodium-hydrogen transporter gene, NHE1, 225 stargazer and GRIA4 knockout mice, 242, 242t thalamocortical network, 229, 230f T-type calcium channels (see T-type calcium channels) Acetylcholine nicotinic receptor CHRNA4, 1–2 LGI1 mutations, 132–133 a4 and b2 subunits, 127 Acetylcholine receptor, 25, 74–75 Actin cytoskeleton glioma cells, 170 idiopathic epilepsies, 168–169 LGI1, 161–162 ADAM22 AMPA receptors, 167–168 LGI1, 167 NgR1, 170–172 ADAM23 EPTP domains, 167 LGI1, 170–172 seizure phenotype, 129–130 ADEAF See Autosomal dominant epilepsy with auditory features (ADEAF) A disintegrin and metalloproteinase (ADAM) basal dendrites, 170–172 LGI1, 167 metalloproteinases, 166 ADJME See Autosomal dominant juvenile myoclonic epilepsy (ADJME) ADNFLE See Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) ADTLE See Autosomal dominant lateral temporal lobe epilepsy (ADTLE) AISs See Axon initial segments (AISs) Allelic heterogeneity, 203, 204 Alpha-thalassemia/mental retardation (ATRX), 291–292 a-Amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors ADAM22/23 transmembrane proteins, 126, 167–168, 173 fast-spiking interneurons, 229, 230f glutamate, 235f GRIA4 knockout mice, 236 polygenic GAERS model, 240 stargazer model, 236–237 subunit GluA2, 236 Angelman syndrome EEG abnormalities, 65–66 GABRB3, 65–66 genetic mechanism, 66 maternal 15q1113, 65 15q13.3 microdeletion, 259–261 UBE3A, 285, 292 Antiepileptic therapies, Kv7 channels drug administration and optimization, 41 hiPSCs, 42 M-current, 38 proteins, 41 retigabine (RTG), 38–41 voltage-gated potassium channel Kv1.1, 42 ATRX See Alpha-thalassemia/mental retardation (ATRX) Autosomal dominant epilepsy with auditory features (ADEAF), 124, 125–126 Autosomal dominant focal epilepsies ADNFLE, 126–127 description, 124, 124f FFEVF, 127–129 TLE, 124–126 Autosomal dominant juvenile myoclonic epilepsy (ADJME) A322D mutation, transmembrane domain, 60 ERAD, 60 317 318 Index Autosomal dominant lateral temporal lobe epilepsy (ADTLE) LGI1, 161 mammalian brain development, 170 secretion, 164 Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) BFNCs, 1–2 CHRNA4 and CHRNB2 genes, 2–4 CHRNA2 gene, DEPDC5 gene, 9–11 FFEVF, 128–129 KCNT1 mutations, 6–9, 127 nAChR-caused, clinical spectrum, 4–5 phenotypes, 1–2, 3t polymorphic markers, 1–2 psychiatric symptoms, 126 Xenopus oocytes, in vitro expression, 127 Axon initial segments (AISs) action potentials, 27, 27f ankyrin G knock-out mice, 27 confocal imaging and patch clamp recordings, 28 Nav1.1, 18 Nav1.2, 28 B Bacterial artificial chromosome (BAC) cortical interneurons, 234–235 GFP, 168–169 LGI1, 164 Batten, 115–116, 115f Benign familial infantile seizures (BFIS) cerebral cortex and basal ganglia, 152–153 chromosome 16p11.2-q12.1, 141–142 ICCA, 259–261 ID, 146 PRRT2, 265 Benign familial neonatal convulsions (BFNCs), 1–2 Benign familial neonatal-infantile seizures (BFNISs) KCNQ2/3 mutations, 30 PRRT2 mutations, 151–152 voltage-gated sodium channels, 97–98, 100, 101 Benign familial neonatal seizures (BFNSs) clinical features and genetics, 30–31 C-terminal mutations, 36 and myokymia, 37 pathogenic mechanisms, 31–34 SCN2A and PRRT2, 30 Benign form of mesial TLE (bMTLE), 124–125 BFIS See Benign familial infantile seizures (BFIS) BFNCs See Benign familial neonatal convulsions (BFNCs) BFNSs See Benign familial neonatal seizures (BFNSs) bMTLE See Benign form of mesial TLE (bMTLE) BRD2 chromosome 6p21, 205 EEG, 205 exon2a, 205–206 JME, 205 knockout mouse model, 206 seizure susceptibility, 206 transcription factor element, 205–206 C CACNA1A gene absence seizures, 93–94 allelic diseases, 92–93 Cav2.1 calcium channel, 153 EA2, 93 FHM, 93 heterozygous mutation, 93 N-type and R-type calcium channels, 239 SCA6, 93 CAE See Childhood absence epilepsy (CAE) Calcium channels ancillary subunits, 94 genes and diseases, 88–89, 89t HVA, 88–91, 90f idiopathic syndromes, 87–88 LVA, 88–90, 90f P/Q-type, 92–94 T-type, 91–92 Childhood absence epilepsy (CAE) C57BL/6J, 62 exon 1a and exon 1, 64 GARBR3, 211 genes, rodent models, 228, 229t HEK293T cells, 64–65 human genetic studies, 228 hyperglycosylation, 64–65 PRRT2 mutation, 146 P11S, S15F and G32R, 64 R82Q mutation, 66–70 R46W mutation, 62 S326fs328*, 61 b3 subunit, 63 Chromatin remodeling ATRX, 291–292 DNA methylation, 294 neuronal cell nucleus, 294 Clinical spectrum, nAChR-caused ADNFLE, 4–5 Copy number variations (CNVs) BRD2, 213 Index chromosome 15q13, 209 EFHC1 gene, 213 genome, 209 IGE, 209, 213 neurodevelopmental disorders, 210, 213 neuropsychiatric diseases, 210 phenotypes, 210 recurrent/nonrecurrent, 261–262 Cortical dysplasia idiopathic epilepsies, 168–169 macroscopic neuroanatomy, 191 Creb-binding protein (CREBBP), 288–289, 294–296 D Dentatorubropallidoluysian atrophy (DRPLA), 119–120 DEPDC5 autism spectrum disorder, disheveled (Dsh), Egl-10 and pleckstrin, glioblastomas and ovarian cancers, 132 LGI1 gene, 10 mRNA degradation, mTOR signaling pathway, 10–11, 131, 131f pathophysiological mechanisms, 132 polymorphism rs1012068, 9–10 tuberous sclerosis and PMSE, 131–132 whole-exome sequencing, 129–131 Disinhibition absence epilepsy (see Absence epilepsy) dementia, 117 GABAA receptor, 237–238 thalamus, 236 DNA methylation 5-aza-cytidine (5-aza-C), 296–297 carboxypeptidase A6 (CPA6), 296–297 classification, 281 CpG dinucleotides, 281 DNMT activity, 301–302 downstream effects, 281–282 H3K9-and H3K27-trimethylation, 284 5-hydroxymethylcytosine (5-hmC), 282 MeCP2, MBD5 and DNMT1, 292–293 Rett syndrome, 282–283 S-adenosyl methionine (SAM), 280 Dominant-negative effect haploinsufficiency mechanism, 24 KCNQ2, 29 KV7.2 mutation, 33 Dravet syndrome and GEFS+, 71 iPSC, 104 myoclonic seizures, 101 parental mosaicism, 101 psychomotor development, 100–101 Q40*, 71–72 Q390*, 71, 72 SCN1A gene, 100–101, 102 a1 subunit, Nav1.1 sodium channels, 74 DRPLA See Dentatorubropallidoluysian atrophy (DRPLA) E EA-1 See Episodic ataxia type (EA-1) EA-2 See Episodic ataxia type (EA-2) EEs See Epileptic encephalopathies (EEs) EFHC1 BRD2, 206–207 CNV studies, 213 JME, 207–208 Electroencephalography (EEG) basal ganglia, 35 BRD2, 205 hypsarrhythmia, 65 JME, 207–208 LD, 117 Elongator protein (ELP4) BRD2, 206–207 CNVs, 207 EEG, 206–207 endophenotype, 206–207 Endoplasmic reticulum-associated degradation (ERAD) a1A322D, 60 Q390*, 72 S326fs328*, 61 Epigenetic mechanisms chromatin structure, 280 CNS development and brain function, 288–289 description, 279–280 DNA methylation, 280–283 histone modifications, 283–285 IGE and EE, 289–293 metabolism and epigenome, 297–301 ncRNAS, 285–288 TLE, 293–297 Epilepsy syndrome ADTLE, 160–161 allelic heterogeneity, 203, 204 amino acids, 161 BRD2 (see BRD2) CAE, 211 CNVs, 209–211 319 320 Index Epilepsy syndrome (Continued) ELP4 and centrotemporal spikes/rolandic epilepsy, 206–207 exome sequencing, 202 genetic technology, 200 GWAS, 200, 203 Hex A, 212 human genome sequence, 200 idiopathic partial epilepsy, 161 JME, 207–208 linkage analysis (see Linkage analysis) neurodevelopmental disorders, 200–201 pathogenicity, 211 TSD, 212 Epileptic encephalopathies (EEs) vs BFNS, 37 de novo mutations, 35 drug candidates, retigabine, 36–37 R213Q mutation, 36 S4 and pore mutations, 36 syndromes, 35 Episodic ataxia type (EA-1), 21–22, 37 Episodic ataxia type (EA-2), 92–93 Epitempin (EPTP), 162 ERAD See Endoplasmic reticulum-associated degradation (ERAD) Exome de novo mutation, 266, 267f disadvantages, 203 gene panels, 265–266 genetic variants, 256 GGE/IGE, 262–263 screening technologies, 255 West syndrome and Lennox–Gastaut syndrome, 267–268 F Familial epilepsies DEPDC5, 265 PRRT2, 265 TBC1D24, 264–265 Familial focal epilepsy with variable foci (FFEVF) DEPDC5 mutations, 129–130 diagnosis, 128–129 linkage, chromosome 22q12, 129 seizure types and epileptic EEG localization, 127–128, 128f Familial hemiplegic migraine (FHM), 92–93 FCD See Focal cortical dysplasia (FCD) Febrile seizure (FS) CPA6, 296–297 D219N, 61 Dravet syndrome, 71, 72 E177A, 73 pathomechanisms, in vitro, 75 R136*, 70 R82Q mutation (see R82Q mutation) SCN1A, 102 S326fs328*, 61 Feedforward inhibition, absence epilepsy AMPA receptors, 236–237 CACNA1A, GRIA4 and GABARA1, 239 CACNB4, GRIA4 and GABRA1, 238–239 Emx1Cre/MeCP2 deletion, 241 GABAA receptor, 235f, 237 monosynaptic excitation and disynaptic inhibition, 238 pharmacologic models, 240–241 polygenic GAERS model, 240, 242 P/Q channels, thalamocortical loop, 241 thalamic relay neurons, 239–240 thalamic stimulation, tottering mice, 234, 235–236 tonic inhibition, CACNG2/GRIA4, 232f, 239 FFEVF See Familial focal epilepsy with variable foci (FFEVF) FHM See Familial hemiplegic migraine (FHM) Focal cortical dysplasia (FCD) dendritic bundles, 186 dysplastic cortex, 186–187 ganglionic eminence, 187 intracortical modules, 186 radial microcolumnar, 184 RELN, 184–185 serotonin (5-hydroxytryptamine), 185 thalamocortical, 185–186 FS See Febrile seizure (FS) G GABAA receptors See g-aminobutyric acid receptor type A (GABAA) receptors GABRA1 ADJME, 60 GGE, 61 IS, 61–62 spike-wave seizures, 238–239 GABRA6 CAE, 62 a6 disruption, 62–63 a1 subunit-deficient mice, 62 GABRB1, 63 GABRB3 Angelman syndrome, 65–66 CAE, 64–65 IS, 65 b3 subunit, 238 Index g-aminobutyric acid receptor type A (GABAA) receptors drugs and substances, 58 dysfunctions, 58 GABAergic neurons and epileptogenesis, 74 GABRA1, 60–62 GABRA6, 62–63 GABRB1, 63 GABRB3, 64–66 in vivo experiments, 75 intracellular Cl¯ concentration, 57–58 mutations and genetic variations, 58–59 neural acetylcholine receptors, 74–75 phasic inhibition, 57–58 structure, 56, 56f a subunit, 60–63 b subunit, 63–66 d subunit, 73–74 g subunit, 66–73 subunit types, 57 Ganglioglioma (GG), 190–191 Gaucher disease, 118–119 Gene regulation, 279–280, 287, 289 Genetic association, 204, 228 Genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome, 71 E177A, 73 K328M, 70 R136*, 70 R220C, 73 R323Q, 70–71 SCN1A and SCN2A, 100–101, 102 W429*, 71 Y444Mfs51*, 71 Genetic (idiopathic) generalized epilepsy (GGE) description, 61 D219N, 61 K353delins18*, 61 N79S, 72–73 P11S, 64 P83S, 73 15q13.3 microdeletion, 256–258 R220H, 73–74 S326fs328*, 61 T-type calcium channels, 92 Genome sequencing, 200, 265–266 Genome-wide association studies (GWASs) AEDs, 263 candidate genes, 262–263, 262t exome sequencing analysis, 203 genetic risk factors, 263 Genomics BFIS, 144 CNVs, 209, 210 exome, 255 Gabrb3, 66 vs genetics, 253–255 genetic variation, 256–257 GWASs, 262–263 massive parallel sequencing, 263–268 microdeletions (see Microdeletions) GGE See Genetic (idiopathic) generalized epilepsy (GGE) Golgi SNAP receptor complex protein gene (GOSR2), 120 GWASs See Genome-wide association studies (GWASs) H Haploinsufficiency autosomal inheritance, 60 DEPDC5 mutations, 130–131 KV7.2/KV7.3, 36 LGI1 mutations, 125–126 PRRT2, 151 HDACs See Histone deacetylases (HDACs) Hemimegalencephaly (HME) GG, 190–191 infantile tauopathies, 189–190 neurocutaneous syndromes, 190 Hemiplegic migraine (HM) ICCA, 146 paroxysmal dyskinesia, 145–146 PRRT2 mutations, 145–146 sporadic/autosomal, 145–146 Heterologous expression, 29, 102–103 Hexosaminidase A (Hex A), 212 High-voltage-activated (HVA) calcium channels activation and deactivation, LVA, 89–90 ancillary subunits, 88–89, 90f, 94 neurotransmitter release, 90–91 Hippocampus AMPA, 126 GABAA receptors, 66, 67–68 LGI1, 94–95 TLE, 91, 293–294 hiPSCs See Human-induced pluripotent stem cells (hiPSCs) Histone deacetylases (HDACs) classification, 302 H3K4 dimethylation, 284 b-hydroxybutyrate, 298–300 and NAD+, 298, 299f pilocarpine, 284 321 322 Index Histones acetyl-CoA and NAD+, 298, 299f chromatin structure, 280 Creb1, 294–296 EHMT1, 292 gene expression, 283 Gria2 and Bdnf promoters, 294 HATs and HDACs, 283 H2A ubiquitination, 284–285 H3K9, H3K27 and H4K20 methylation, 284 KDM5C mutations, 302 learning and memory, 288–289 perturbations, 285 HM See Hemiplegic migraine (HM) HME See Hemimegalencephaly (HME) Human-induced pluripotent stem cells (hiPSCs), 42 HVA calcium channels See High-voltage-activated (HVA) calcium channels I ICCA See Infantile convulsions and choreoathetosis (ICCA) ID See Intellectual disability (ID) Idiopathic generalized epilepsy (IGE) chromatin remodelers, 291–292 chromosome 15q11-14, 209 disorders, brain development, 289–290, 290t DNA methylation, 292–293 GWAS, 201–202 histone methyltransferase, EHMT1, 292 microdeletion, 256–258 SCN1A, 262–263 voltage-/ligand-gated ion channels, 289–290 IGE See Idiopathic generalized epilepsy (IGE) Induced pluripotent stem cell (iPSC) method Dravet syndrome, 104 whole-exome sequencing, 103–104 Infantile convulsions and choreoathetosis (ICCA) ID, 146 PKD, 144 PRRT2, 144, 148t Infantile spasms (ISs) F246S, 63 N25D, D35N, E109G and Y302C, 65 T292I, de novo mutation, 61–62 Intellectual disability (ID) EHMT1, 292 FFEVF, 127–128 KCNT1, 6–7 PRRT2 mutation, 146 SCN2A de novo mutations, 268 Ion channel ADNFLE, 11 anticonvulsants, 18 channelopathies, 21 CHRNA4, 127 potassium (K+), 19 voltage-gate, 18 iPSC method See Induced pluripotent stem cell (iPSC) method ISs See Infantile spasms (ISs) J Juvenile myoclonic epilepsy (JME) autosomal dominant, 60 EEGs, 207–208 Mexicans and EFHC1, 207–208 mouse model, 208 K KCNQ2/3 mutations BFNSs, 30–34 EE, 34–37 knock-in models, 29 knock-out models, 28, 29 M-current, 23–24 PNH, 37–38 KCNT1 gene COOH-terminal region, de novo mutations, 7–8 genotype-phenotype relationships, 8–9 Gly288Ser and Arg428Gln, 7–8 intellectual disability, 6–7 KCa4.1 channels, malignant migrating partial seizures of infancy, 6–8 Kuf, 116 Kv7.2/7.3 channels AISs (see Axon initial segments (AISs)) assembly, 26 description, 31, 32f expression patterns, 34 haploinsufficiency, gating alterations and dominant-negative effect, 31, 32f, 33 molecular mechanisms, 25–26 N-and C-terminal domains, 25, 33 regulation, M-current, 26–27 S4 voltage sensor, 33, 34 TEA sensitivity, 25 wild-type (WT), coexpression, 31–33 Xenopus oocytes, 25 Kv7 voltage-gated potassium channels antiepileptic therapies, 38–42 Index KCNQ1, 23 KCNQ4, 24 KCNQ5, 24 KCNQ2 and KCNQ3, 23–24 Kv7.2/7.3 (see Kv7.2/7.3 channels) retigabine (RTG), 38–41 L Lafora disease (LD), 117 Lennox–Gastaut syndrome (LGS), 65, 210, 267–268 Leucine-rich glioma inactivated (LGI1) actin cytoskeleton, 161–162 ADAM, 166 BAC, 164 cancer cell motility, 161–162 colocalization, 169 cortical development, 168–169 EEG recordings, 163 epitempin (EPTP), 162, 167 gene ablation studies, 163 limbic encephalitis, 167–168 mammalian brain development, 170–172 neurocorticogenesis, 169 NPC, 161–162 peripheral nervous system, 167 PSD95, 167 PTZ, 163–164 secretory protein, 162 synaptic transmission, 165–166 T98G glioma cell, 161–162 zebrafish, 164–165 LGI1 See Leucine-rich glioma inactivated (LGI1) LGS See Lennox–Gastaut syndrome (LGS) Limbic encephalitis, 167–168 Linkage analysis allelic heterogeneity, 203 chromosomal region, 201–202 exon, 201–202 IGE, 202–203 locus, 202–203, 204 mutations, 202 pathogenicity, 201–202 small families, 204 Long ncRNAs, 287–288 Long QT syndrome (LQTS), 23 Low-voltage activated (LVA) calcium channels, 88–90, 90f M Malformations cerebral development, 187 FCDs, 184–187 frontal neocortex, 189–190, 189f GG, 190–191 HME, 183, 189–190 MAPs, 188–189 membrane potential, 183–184 microtubules, 189–190 myelination, 182 neurological dysfunction, 182 precocious synapse formation, 183 somatic mosaicism, 190 synaptophysin immunoreactivity, 182–183 tauopathies, 189–190, 189f Mammalian brain development, LGI1 actin cytoskeleton, 170 ADTLE, 170 cortical dysplasias, 170 mutant null mice, 170, 171f myelin, 170–172 NgR1, 170–172 Mammalian target of rapamycin (mTOR) cell growth, 10–11 DEPDC5, 10 tuberous sclerosis, 131–132 MAPs See Microtubule-associated proteins (MAPs) Massive parallel sequencing exome, 255 family studies, 264–265 genes, human epilepsies, 263–264, 264t panel studies, 265–266 trio studies, 266–268 M-current KV7.3 channels, 25 membrane potential, 25 neuronal firing, 34 potassium current, 20–21 Metabolism acetyl-CoA and NAD+, 298, 299f folate and adenosine, 300 glucose, 297–298, 299f HAT and HDAC activity, 298–300 production and availability, 300–301 Methylmalonic acidemia, 191 Microdeletions chromosome 22q11.2, 187, 188f genomic disorders, 259–261, 260f ID and autism, 261–262 pathogenic CNVs, 261 15q13.3, 256–257 recurrent and nonrecurrent, 258–259 SNP arrays, 257–258, 258f Microtubule-associated proteins (MAPs), 188–189 323 324 Index Migraine Cav2.1 gene, 92 FHM, 92–93 PRRT2 mutations, 146 Morpholinos (MO), 164–165 N nAChRs See Nicotinic acetylcholine receptors (nAChRs) ncRNAs See Noncoding RNAs (ncRNAs) Neuronal ceroid lipofuscinoses (NCL) categorization, 114 CLN4, 116 curvilinear profiles, CLN2, 90f, 114–115 description, 114 granular osmiophilic deposits, 90f, 114 lysosomal storage diseases, 116 vacuolation, lymphocytes, 90f, 115–116 Neuroprogenitor cells (NPC), 161–162 Nicotinic acetylcholine receptors (nAChRs) CHRNA4 and CHRNB2 genes, 2–4 CHRNA2 mutation Ile279Asn, clinical spectrum, ADNFLE, 4–5 DEPDC5, Nocturnal frontal lobe epilepsy ADNFLE (see Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)) DEPDC5, 132–133 Noncoding RNAs (ncRNAs) description, 285–286 long, 287–288 piRNAs, 288–289 small, 286 North Sea PME, 120 NPC See Neuroprogenitor cells (NPC) Nuclear receptor binding SET domain protein (NSD1), 292 P Paroxysmal dyskinesia, 22 Paroxysmal exercised-induced dyskinesia (PED), 144–145 Paroxysmal kinesigenic dyskinesia (PKD) basal ganglia disorders, 143 channelopathy, 143 choreoathetoid, 142 EEGs, 142–143 familial disorder, 142 lobectomy, 142–143 potassium channel gene (KCNA1), 143 PED See Paroxysmal exercised-induced dyskinesia (PED) Pentylenetetrazol (PTZ) ADAM23, 166 forebrain and optic tectum, 164–165 lgi1b morphants, 165 Peripheral motor neurons (PNH), 30, 32f, 37–38 PIWI-interacting RNAs (piRNAs), 285–286, 288–289 PKD See Paroxysmal kinesigenic dyskinesia (PKD) PME See Progressive myoclonus epilepsies (PME) PNH See Peripheral motor neurons (PNH) Polycomb and trithorax group proteins, 288 Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE), 131–132 Potassium (K+) channels GYG signature sequence, 19 Kv4.2, 22 Kv1.1 mutations, episodic ataxia, 21–22 membrane potential, 17–18 Nav channels, 20–21 neuronal disorders, 21 neurons and glial cells, 21 neurotransmitters, 18 paroxysmal dyskinesia, KCa1.1 mutation, 22 physiological functions, 18–19 structure and function, Kv, 19–20, 20f subunits, 19 transmembrane (TM), 19 P/Q-type calcium channels CACNA1A gene (see CACNA1A gene) loss-of-function mutations, 233–234 RTN neurons, 235–236 SNAP-25 mutations, 233–234 thalamic stimulation, tottering mice, 234 Progressive myoclonus epilepsies (PME) action myoclonus-renal failure syndrome, 119 description, 113–114 DRPLA, 119–120 LD, 117 mitochondrial disease, 119 NCL, 114–116 neuronopathic Gaucher disease, 118–119 North Sea, 120 SMA, 120 type I sialidosis, 118 ULD, 116–117 Proline-rich transmembrane protein (PRRT2) amino acid, 151 benign familial neonatal-infantile, 151–152 benign infantile seizures, 145 BFIS, 143–144 c.649dupC mutation, 151 chromosome 16p11.2, 146–151 exon and 3, 146–151 Index HM, 145–146 ICCA syndrome, 144 ID, 146 in situ hybridization, 152–153 interfamilial and intrafamilial, 151 messenger RNA, 151 mutations, 146–152 neurological disorders, 141–142 nonsense and frameshift mutations, 152, 152f PKD, 142–143 PNKD and PED, 144–145 reverse transcriptase polymerase chain reaction, 152–153 single-nucleotide, 147f, 151 SNAP25, 153 TM, 152 Psychiatric symptoms, 126 PTZ See Pentylenetetrazol (PTZ) Q 15q13.3 Microdeletion CNVs, 258–259 genome wide, 257–258 recurrent and nonrecurrent, 258–259 S SCA6 See Spinocerebellar ataxia type (SCA6) SCN1A Dravet syndrome, 71 GABAergic neurons, 74 voltage-gated sodium channel, 98–99 Seizures BFNS, 34 EEG, 127–128 epileptic phenotype, 298 Sialidosis, 118 Single nucleotide polymorphisms (SNPs) BRD2, 205 ELP4, 207 microdeletions, 257–258, 258f P11S, 64 Small ncRNAs, 286 SNAP25 See Synaptosomal-associated protein 25 kDa (SNAP25) SNPs See Single nucleotide polymorphisms (SNPs) Spinal muscular atrophy (SMA), 120 Spinocerebellar ataxia type (SCA6), 92–93 Synapse function, 166, 173 Synaptophysin immunoreactivity, 187 Synaptosomal-associated protein 25 kDa (SNAP25), 153 R T Ragged red fibers, 119 Reelin gene (RELN), 184–185, 296–297 Renal failure syndrome, 119 Retigabine ezogabine, 38–39 gating hinge, 39–40 KV7.2 channel, 35, 39–40 novel antiepileptic drug, 43 Rolandic epilepsy (RE), 208–209 channelopathies, 30 CNVs, 207 ELP4, 206–207 JME, 207–208 R82Q mutation benzodiazepine, 67 GDP, 69 granule cell layer, 69 human CAE and thermal sensitivity, 68 intracellular retention, 68 mIPSCs, 69 phasic and tonic inhibitions, 67–68 seizure development, 69 g2 subunits, 69–70 temperature, 67 Rubinstein–Taybi syndrome, 288–289 Tay-Sachs disease (TSD), 212 Temporal lobe epilepsy (TLE) ADEAF, 125–126 adenosine augmentation, 296–297 Bdnf and Gria2 gene expression, 294 bMTLE, 124–125 brain inflammation, 296 candidate genes, 294 CA1 pyramidal cells, 91–92 carboxypeptidase A6 (CPA6), 296–297 chromosomes 12q22-q23, 18q and 1q25-q31, 124–125 classification, 124 DEPDC5 mutations, 129–130 gene expression profiling, 293–294, 295f hippocampal sclerosis, 293–294 histone acetylation and IEG expression, 294–296 LGI1 protein, 126 miR-146a, 286 TLE See Temporal lobe epilepsy (TLE) Tonic inhibition absence epilepsy, 240–241 calcium channels, 231–233 GABAA receptor, 62–63 thalamocortical circuit, 235–236 325 326 Index Transcription factor element, 205–206 TSD See Tay-Sachs disease (TSD) T-type calcium channels CACNA1G and CACNA1H, 231 CACNA1H gene, 91 ethosuximide, 229–231 GABAA receptors, 233 GABAB receptors, 233 GAT-1 protein, 231–233, 232f GGE and TLE, 91–92 LVA, 89–90 rat Cav3.2 gene (R1584P), 92 stargazer, tottering and coloboma models, 231 WAG/Rij rat model, 231 U Unverricht–Lundborg disease (ULD), 116–117 V Variable foci DEPDC5, 265 FFEVF, 127–129 Voltage-gated sodium channels benign familial neonatal-infantile seizures, 100 Dravet syndrome (see Dravet syndrome) epilepsy phenotypes, 97–98, 98t expression pattern, 100 GEFS+, 101, 102 intracellular loop, 99 membrane potentials and depolarization, 98–99 pathogenetic mechanisms, 102–104 subunits, genes coding, 102 transmembrane domains, 98–99, 99f W West syndrome, 267–268, 292 Z Zebrafish c-fos, 164–165 choroid plexus, 165 gene–phenotype, 164–165 hydrocephalus, 165 MO, 164–165 PTZ, 164–165 Other volumes in PROGRESS IN BRAIN RESEARCH Volume 161: Neurotrauma: New Insights into Pathology and Treatment, by J.T Weber and A.I.R Maas (Eds.) – 2007, ISBN 978-0-444-53017-2 Volume 162: Neurobiology of Hyperthermia, by H.S Sharma (Ed.) – 2007, ISBN 978-0-444-51926-9 Volume 163: The Dentate Gyrus: A Comprehensive Guide to Structure, Function, and Clinical Implications, by H.E Scharfman (Ed.) – 2007, ISBN 978-0-444-53015-8 Volume 164: From Action to Cognition, by C von Hofsten and K Rosander (Eds.) – 2007, ISBN 978-0-444-53016-5 Volume 165: Computational Neuroscience: Theoretical Insights into Brain Function, by P Cisek, T Drew and J.F Kalaska (Eds.) – 2007, ISBN 978-0-444-52823-0 Volume 166: Tinnitus: Pathophysiology and Treatment, by B Langguth, G Hajak, T Kleinjung, A Cacace and A.R 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Angela Cenci (Eds.) 2010, 978-0-444-53750-8 327 328 Other volumes in PROGRESS IN BRAIN RESEARCH Volume 185: Human Sleep and Cognition Part I: Basic Research, by Gerard A Kerkhof and Hans P.A Van Dongen (Eds.) – 2010, 978-0-444-53702-7 Volume 186: Sex Differences in the Human Brain, their Underpinnings and Implications, by Ivanka Savic (Ed.) – 2010, 978-0-444-53630-3 Volume 187: Breathe, Walk and Chew: The Neural Challenge: Part I, by Jean-Pierre Gossard, Re´jean Dubuc and Arlette Kolta (Eds.) – 2010, 978-0-444-53613-6 Volume 188: Breathe, Walk and Chew; The Neural Challenge: Part II, by Jean-Pierre Gossard, Re´jean Dubuc and Arlette Kolta (Eds.) – 2011, 978-0-444-53825-3 Volume 189: Gene Expression to Neurobiology and Behaviour: Human Brain Development and Developmental Disorders, by Oliver Braddick, Janette Atkinson and Giorgio M Innocenti (Eds.) – 2011, 978-0-444-53884-0 Volume 190: Human Sleep and Cognition Part II: Clinical and Applied Research, by Hans P.A Van Dongen and Gerard A Kerkhof (Eds.) – 2011, 978-0-444-53817-8 Volume 191: Enhancing Performance for Action and perception: Multisensory Integration, Neuroplasticity and Neuroprosthetics: Part I, by Andrea M Green, C Elaine Chapman, John F Kalaska and Franco Lepore (Eds.) – 2011, 978-0-444-53752-2 Volume 192: Enhancing Performance for Action and Perception: Multisensory Integration, Neuroplasticity and Neuroprosthetics: Part II, by Andrea M Green, C Elaine Chapman, John F Kalaska and Franco Lepore (Eds.) – 2011, 978-0-444-53355-5 Volume 193: Slow Brain Oscillations of Sleep, Resting State and Vigilance, by Eus J.W Van Someren, Ysbrand D Van Der Werf, Pieter R Roelfsema, Huibert D Mansvelder and Fernando H Lopes da Silva (Eds.) – 2011, 978-0-444-53839-0 Volume 194: Brain Machine Interfaces: Implications For Science, Clinical Practice And Society, by Jens Schouenborg, Martin Garwicz and Nils Danielsen (Eds.) – 2011, 978-0-444-53815-4 Volume 195: Evolution of the Primate Brain: From Neuron to Behavior, by Michel A Hofman and Dean Falk (Eds.) – 2012, 978-0-444-53860-4 Volume 196: Optogenetics: Tools for Controlling and Monitoring Neuronal Activity, by Thomas Knoăpfel and Edward S Boyden (Eds.) – 2012, 978-0-444-59426-6 Volume 197: Down Syndrome: From Understanding the Neurobiology to Therapy, by Mara Dierssen and Rafael De La Torre (Eds.) – 2012, 978-0-444-54299-1 Volume 198: Orexin/Hypocretin System, by Anantha Shekhar (Ed.) – 2012, 978-0-444-59489-1 Volume 199: The Neurobiology of Circadian Timing, by Andries Kalsbeek, Martha Merrow, Till Roenneberg and Russell G Foster (Eds.) – 2012, 978-0-444-59427-3 Volume 200: Functional Neural Transplantation III: Primary and stem cell therapies for brain repair, Part I, by Stephen B Dunnett and Anders Bjoărklund (Eds.) 2012, 978-0-444-59575-1 Volume 201: Functional Neural Transplantation III: Primary and stem cell therapies for brain repair, Part II, by Stephen B Dunnett and Anders Bjoărklund (Eds.) 2012, 978-0-444-59544-7 Volume 202: Decision Making: Neural and Behavioural Approaches, by V.S Chandrasekhar Pammi and Narayanan Srinivasan (Eds.) – 2013, 978-0-444-62604-2 Volume 203: The Fine Arts, Neurology, and Neuroscience: Neuro-Historical Dimensions, by Stanley Finger, Dahlia W Zaidel, Franc¸ois Boller and Julien Bogousslavsky (Eds.) – 2013, 978-0-444-62730-8 Volume 204: The Fine Arts, Neurology, and Neuroscience: New Discoveries and Changing Landscapes, by Stanley Finger, Dahlia W Zaidel, Franc¸ois Boller and Julien Bogousslavsky (Eds.) – 2013, 978-0-444-63287-6 Volume 205: Literature, Neurology, and Neuroscience: Historical and Literary Connections, by Anne Stiles, Stanley Finger and Franc¸ois Boller (Eds.) – 2013, 978-0-444-63273-9 Volume 206: Literature, Neurology, and Neuroscience: Neurological and Psychiatric Disorders, by Stanley Finger, Franc¸ois Boller and Anne Stiles (Eds.) – 2013, 978-0-444-63364-4 Volume 207: Changing Brains: Applying Brain Plasticity to Advance and Recover Human Ability, by Michael M Merzenich, Mor Nahum and Thomas M Van Vleet (Eds.) – 2013, 978-0-444-63327-9 Other volumes in PROGRESS IN BRAIN RESEARCH Volume 208: Odor Memory and Perception, by Edi Barkai and Donald A Wilson (Eds.) – 2014, 978-0-444-63350-7 Volume 209: The Central Nervous System Control of Respiration, by Gert Holstege, Caroline M Beers and Hari H Subramanian (Eds.) – 2014, 978-0-444-63274-6 Volume 210: Cerebellar Learning, Narender Ramnani (Ed.) – 2014, 978-0-444-63356-9 Volume 211: Dopamine, by Marco Diana, Gaetano Di Chiara and Pierfranco Spano (Eds.) – 2014, 978-0-444-63425-2 Volume 212: Breathing, Emotion and Evolution, by Gert Holstege, Caroline M Beers and Hari H Subramanian (Eds.) – 2014, 978-0-444-63488-7 329 ... Mutations within the COOH terminus might introduce conformational alterations that could interfere with the binding of FMRP, causing changes in the firing pattern of neurons expressing the KCa4.1... synthesized during the clinical evaluation of flupirtine was proven to be specifically binding to the pore sequence of KCNQ channels expressed in brain and has recently been introduced into the market... 1996; Sanguinetti et al., 1996) Besides in the heart, KV7.1/KCNE1 channels are expressed in the inner ear, thyroid gland, lung, gastrointestinal tract, the small intestine, pancreas, forebrain neuronal