Pathophysiologie der Epilepsie

Zusammenfassung

Die Epilepsieforschung ist kein neues wissenschaftliches Feld - klinische und experimentelle Untersuchungen werden seit Jahrzehnten betrieben. Trotz dieser fortwährenden Bemühungen sind die Pathomechanismen der Epilepsie letztlich nicht vollständig geklärt - allerdings gelangen in den letzten Jahren auch beachtliche Fortschritte. Vor allem durch die Kombination genetischer, molekularer und funktioneller Analysen konnten wichtige Teilaspekte der Entstehungsprozesse der Epilepsie aufgeklärt werden. Der vorliegende Übersichtsartikel soll nach einer kurzen Erörterung der grundsätzlichen Faktoren der Erregbarkeit einzelner Zellen und des neuronalen Zellverbandes in fünf kurzen Kapiteln einen Überblick über den aktuellen Forschungsstand liefern. Innerhalb der ersten drei Abschnitte werden Veränderungen spannungsabhängiger Ströme, der synaptischen Transmission und deren Modulation sowie der Expression von Gap junctions beleuchtet. Darüber hinaus widmet sich ein Abschnitt morphologischen Veränderungen. Der letzte Teil behandelt Aspekte spezifischer genetischer Syndrome.

Abstract

Epilepsy research is not a recent scientific field - indeed clinical and experimental investigations in epileptology have been carried out for decades. In spite of these continued efforts, the pathomechanisms underlying epilepsy have so far remained elusive. However, the recent years have brought significant advances, such that important aspects of epileptic discharges and epileptogenesis have been unveiled. The present paper aims to review the current state of the field. Beginning with an introductory section on general principles of neuronal and network excitability, contributing factors such as changes of voltage-gated currents, of synaptic transmission and of gap-junction function will be highlighted. Furthermore, one section is devoted to morphological changes, and the fifth to specific genetic syndromes.

Key words

epilepsy - neuronal excitability - bursting - I_m - I_h - persistent sodium current - synaptic plasticity - NMDA - GABA - sprouting

Literatur

• 1 Avoli M, Louvel J, Pumain R, Köhling R. Cellular and molecular mechanisms of epilepsy in the human brain.  Prog Neurobiol. 2005;  77 166-200
• 2 Su H, Sochivko D, Becker A, Chen J, Jiang Y, Yaari Y, Beck H. Upregulation of a T-Type Ca²⁺ Channel causes a long-lasting modification of neuronal firing mode after status epilepticus.  J Neurosci. 2002;  22 3645-3655
• 3 Beck H, Steffens R, Heinemann U, Elger C E. Properties of voltage-activated Ca²⁺ currents in acutely isolated human hippocampal granule cells.  Am Physiol Society. 1996;  Vol 1-12
• 4 Beck H, Steffens R, Elger C E, Heinemann U. Voltage-dependent Ca²⁺ currents in epilepsy.  Epilepsy Res. 1998;  32 321-332
• 5 Sanabria E RC, Su H L, Yaari Y. Initiation of network bursts by Ca²⁺-dependent intrinsic bursting in the rat pilocarpine model of temporal lobe epilepsy.  Journal of Physiology-London. 2001;  532 205-216
• 6 Khosravani H, Altier C, Simms B. et al . Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy.  J Biol Chem. 2004;  279 9681-9684
• 7 Reckziegel G, Beck H, Schramm J, Elger C E, Urban B W. Properties of voltage-dependent sodium channels (INa) in isolated human hippocampal neurones. 1998
• 8 Vreugdenhil M, Hoogland G, Veelen C W van, Wadman W J. Persistent sodium current in subicular neurons isolated from patients with temporal lobe epilepsy.  Eur J Neurosci. 2004;  19 2769-2778
• 9 Chen K, Aradi I, Thon N, Eghbal-Ahmadi M, Baram T Z, Soltesz I. Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability.  Nat Med. 2001;  7 331-337
• 10 Strauss U, Kole M H, Brauer A U. et al . An impaired neocortical I_h is associated with enhanced excitability and absence epilepsy.  Eur J Neurosci. 2004;  19 3048-3058
• 11 Bender R A, Soleymani S V, Brewster A L. et al . Enhanced expression of a specific hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) in surviving dentate gyrus granule cells of human and experimental epileptic hippocampus.  J Neurosci. 2003;  23 6826-6836
• 12 Yue C, Yaari Y. KCNQ/M channels control spike after depolarization and burst generation in hippocampal neurons.  J Neurosci. 2004;  24 4614-4624
• 13 Biervert C, Schroeder B C, Kubisch C. et al . A potassium channel mutation in neonatal human epilepsy.  Science. 1998;  279 403-406
• 14 Prince D A. Neurophysiology of Epilepsy.  Ann Rev Neurosci. 1978;  1 395-415
• 15 Köhr G, Koninck Y De, Mody I. Properties of NMDA receptor channels in neurons acutely isolated from epileptic (kindled) rats.  J Neurosci. 1993;  13 3612-3627
• 16 Isokawa M, Levesque M F. Increased NMDA responses and dendritic degeneration in human epileptic hippocampal neurons in slices.  Neurosci Lett. 1991;  132 212-216
• 17 Isokawa M, Levesque M, Fried I, Engel J. Glutamate currents in morphologically identified human dentate granule cells in temporal lobe epilepsy.  J Neurophysiol. 1997;  77 3355-3369
• 18 Mathern G W, Pretorius J K, Mendoza D, Lozada A, Kornblum H I. Hippocampal AMPA and NMDA mRNA levels correlate with aberrant fascia dentata mossy fiber sprouting in the pilocarpine model of spontaneous limbic epilepsy.  J Neurosci Res. 1998;  54 734-753
• 19 Mathern G W, Pretorius J K, Kornblum H I. et al . Human hippocampal AMPA and NMDA mRNA levels in temporal lobe epilepsy patients.  Brain. 1997;  120 1937-1959
• 20 Avoli M, Olivier A. Electrophysiological properties and synaptic responses in the deep layers of the human epileptogenic neocortex in vitro.  J Neurophysiol. 1989;  61, 3 589-606
• 21 Kortenbruck G, Berger E, Speckmann E-J, Musshoff U. RNA Editing at the Q/R Site for the Glutamate Receptor Subunits GLUR2, GLUR5 and GLUR6 in Hippocampus and Temporal Cortex from Epileptic Patients.  Neurobiology of Disease. 2001;  8 459-468
• 22 Dietrich D, Kral T, Clusmann H, Friedl M, Schramm J. Reduced function of L-AP4-sensitive metabotropic glutamate receptors in human epileptic sclerotic hippocampus.  Eur J Neurosci. 1999;  11 1109-1113
• 23 Whittington M A, Traub R D, Jefferys J GR. Erosion of inhibition contributes to the progression of low magnesium bursts in rat hippocampal slices.  J Physiol (Lond). 1995;  486 723-734
• 24 Sloviter R S. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: The „Dormant Basket Cell” hypothesis and its possible relevance to temporal lobe epilepsy.  Hippocampus. 1991;  1 41-66
• 25 McDonald J W, Garofalo E A, Hood T. et al . Altered excitatory and inhibitory amino acid receptor binding in hippocampus of patients with temporal lobe epilepsy.  Ann Neurol. 1991;  29, 5 529-541
• 26 Johnson E W, Lanerolle N C De, Kim J H. et al . „Central” and „peripheral” benzodiazepine receptors: opposite changes in human epileptogenic tissue.  Neurology. 1992;  42 811-815
• 27 Houser C R, Miyashiro J E, Swartz B E, Walsh G O, Rich J R, Delgado-Escueta A V. Altered patterns of dynorphin immunoreactivity suggest mossy fiber reorganization in human hippocampal epilepsy.  The Journal of Neuroscience. 1990;  10 267-282
• 28 Arellano J I, Munoz A, Ballesteros-Yanez I, Sola R G, DeFelipe J. Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus.  Brain. 2004;  127 45-64
• 29 Isokawa M. Decrement of GABA_A receptor-mediated inhibitory postsynaptic currents in dentate granule cells in epileptic hippocampus.  J Neurophysiol. 1996;  75 1901-1908
• 30 Palma E, Ragozzino D A, Angelantonio S Di. et al . Phosphatase inhibitors remove the run-down of γ-aminobutyric acid type A receptors in the human epileptic brain.  PNAS. 2004;  101 10183-10188
• 31 Babb T L, Pretorius J K, Kupfer W R, Crandall P H. Glutamate decarboxylase-immunoreactive neurons are preserved in human epileptic hippocampus.  The Journal of Neuroscience. 1989;  9 2562-2574
• 32 Bernard C, Esclapez M, Hirsch J C, Ben Ari Y. Interneurones are not so dormant in temporal lobe epilepsy: a critical reappraisal of the dormant basket cell hypothesis.  Epilepsy Res. 1998;  32 93-103
• 33 Koch U R, Musshoff U, Pannek H W. et al . Intrinsic excitability, synaptic potentials, and short-term plasticity in human epileptic neocortex.  J Neurosci Res. 2005;  80 715-726
• 34 McCormick D A. GABA as an Inhibitory Neurotransmitter in Human Cerebral Cortex.  journal of neurophysiology. 1989;  62 1018-1027
• 35 Cohen I, Navarro V, Clemenceau S, Baulac M, Miles R. On the origin of interictal activity in human temporal lobe epilepsy in vitro.  Science. 2002;  298 1418-1421
• 36 Köhling R, Vreugdenhil M, Bracci E, Jefferys J GR. Ictal epileptiform activity is facilitated by hippocampal GABA_A receptor-mediated oscillations.  J Neurosci. 2000;  20 6820-6829
• 37 Rivera C, Voipio J, Payne J A. et al . The K⁺/Cl^- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation.  Nature. 1999;  397 251-255
• 38 Rivera C, Li H, Thomas-Crusells J. et al . BDNF-induced TrkB activation down-regulates the K _⁺ -Cl^- cotransporter KCC2 and impairs neuronal Cl^{- extrusion.} .  The Journal of Cell Biology. 2002;  159 747-752
• 39 Köhling R, Lücke A, Straub H. et al . Spontaneous sharp waves in human neocortical slices excised from epileptic patients.  Brain. 1998;  121 1073-1087
• 40 Khalilov I, Holmes G L, Yehezkel B-A. In vitro formation of a secondary epileptogenic mirror focus by interhippocampal propagation of seizures.  Nature Neurosci. 2003;  6 1079-1085
• 41 Boison D. Adenosine and epilepsy: from therapeutic rationale to new therapeutic strategies.  Neuroscientist. 2005;  11 25-36
• 42 Glass M, Faull R LM, Bullock J Y. et al . Loss of A1 adenosine receptors in human temporal lobe epilepsy.  Brain Res. 1996;  710 56-68
• 43 Naus C C, Bechberger J F, Paul D L. Gap junction gene expression in human seizure disorder.  Exp Neurol. 1991;  111 198-203
• 44 Köhling R, Gladwell S J, Bracci E, Vreugdenhil M, Jefferys J G. Prolonged epileptiform bursting induced by 0-Mg(²⁺) in rat hippocampal slices depends on gap junctional coupling.  Neuroscience. 2001;  105 579-587
• 45 Carlen P L, Skinner F, Zhang L, Naus C, Kushnir M, Velazquez J LP. The role of gap junctions in seizures.  Brain Res Rev. 2000;  32 235-241
• 46 Wallraff A, Köhling R, Heinemann U, Theis M, Willecke K, Steinhauser C. The impact of astrocytic gap junctional coupling on potassium buffering in the hippocampus.  J Neurosci. 2006;  26 5438-5447
• 47 Isokawa M. Remodeling dendritic spines of dentate granule cells in temporal lobe epilepsy patients and the rat pilocarpine model.  Epilepsia. 2000;  41, Suppl 6 S14-S17
• 48 Blümcke I, Schewe J C, Normann S. et al . Increase of nestin-immunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early-onset temporal lobe epilepsy.  Hippocampus. 2001;  11 311-321
• 49 Blümcke I, Beck H, Lie A A, Wiestler O D. Molecular neuropathology of human mesial temporal lobe epilepsy.  Epilepsy Res. 1999;  36 205-223
• 50 Haas C A, Dudeck O, Kirsch M. et al . Role for reelin in the development of granule cell dispersion in temporal lobe epilepsy.  J Neurosci. 2002;  22 5797-5802
• 51 Biervert C, Schroeder B C, Kubisch C. et al . A potassium channel mutation in neonatal human epilepsy.  Science. 1998;  279 403-406
• 52 Escayg A, MacDonald B T, Meisler M H. et al . Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+ 2.  Nat Genet. 2000;  24 343-345
• 53 Escayg A, Heils A, MacDonald B T, Haug K, Sander T, Meisler M H. A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus - and prevalence of variants in patients with epilepsy.  Am J Hum Genet. 2001;  68 866-873
• 54 Wallace R H, Wang D W, Singh R. et al . Febrile seizures and generalized epilepsy associated with a mutation in the Na⁺-channel beta1 subunit gene SCN1B.  Nat Genet. 1998;  19 366-370
• 55 Baulac S, Huberfeld G, Gourfinkel-An I. et al . First genetic evidence of GABA_A receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene.  Nature Genet. 2001;  28 46-48
• 56 Phillips H A, Favre I, Kirkpatrick M. et al . CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy.  Am J Hum Genet. 2001;  68 225-231
• 57 Steinlein O K, Mulley J C, Propping P. et al . A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.  Nat Genet. 1995;  11 201-203
• 58 Steinlein O K. Genes and mutations in idiopathic epilepsy.  Am J Med Genet. 2001;  106 139-145
• 59 Aracri P, Colombo E, Mantegazza M. et al . Layer-specific properties of the persistent sodium current in sensorimotor cortex.  J Neurophysiol. 2006;  95 3460-3468
• 60 Robinson R B, Siegelbaum S A. Hyperpolarization-activated cation currents: from molecules to physiological function.  Annu Rev Physiol. 2003;  65 453-480
• 61 Jentsch T J. Neuronal KCNQ potassium channels: physiology and role in disease.  Nat Rev Neurosci. 2000;  1 21-30
• 62 Kullmann D M, Asztely F, Walker M C. The role of mammalian ionotropic receptors in synaptic plasticity: LTP, LTD and epilepsy.  Cell Mol Life Sci. 2000;  57 1551-1561