Article

Neue Entwicklungen der Epileptogenese und therapeutische Perspektiven

Der Nervenarzt (Impact Factor: 0.86). 08/2011; 82(8):978-985. DOI: 10.1007/s00115-011-3260-4

ABSTRACT Die Epileptogenese beschreibt die Entstehungsmechanismen von Epilepsien. Wir haben 4Gebiete ausgewählt, auf denen entscheidende
Fortschritte für das Verständnis der Epileptogenese erzielt wurden. Dies betrifft im Einzelnen (1) inflammatorische Prozesse,
denen bei der Entstehung von Temporallappenepilepsien mit Hippokampussklerose (TLE mit HS) eine zunehmende Bedeutung zukommt,
(2) Störungen intrinsischer Eigenschaften von neuronalen Kompartimenten, v.a. erworbene Störungen von Ionenkanälen, von denen
hier bei der TLE mit HS solche in Dendriten beschrieben werden sollen, (3) epigenetische Effekte, die z.B. die Methylierung
von Promotoren betreffen und dadurch sekundär die Expression bestimmter Gene verändern und die auch bei der TLE mit HS gefunden
werden, und schließlich (4) die Epileptogenese der idiopathischen Epilepsien, die durch angeborene genetische Veränderungen
verursacht werden und überwiegend Ionenkanäle betreffen. Neben grundlagenwissenschaftlichen Aspekten wird auf klinische Konsequenzen
und therapeutische Perspektiven eingegangen.

Epileptogenesis describes the mechanisms of how epilepsies are generated. We have chosen four areas in which significant progress
has been achieved in understanding epileptogenesis. Those are (1) inflammatory processes which play an increasingly important
role for the generation of temporal lobe epilepsy with hippocampal sclerosis (TLE with HS), (2) disturbances of intrinsic
properties of neuronal compartments, in particular acquired defects of ion channels of which those in dendrites are described
here for TLE with HS, (3) epigenetic effects, which affect for example the methylation of promoters and secondarily can change
the expression of specific genes in TLE with HS, and finally (4) the epileptogenesis of idiopathic epilepsies which are caused
by inborn genetic alterations affecting mainly ion channels. Apart from aspects of basic research, we will describe clinical
consequences and therapeutic perspectives.

SchlüsselwörterEpilepsie–Inflammation–Ionenkanal–Epigenetik–Genetik
KeywordsEpilepsy–Inflammation–Ion channel–Epigenetics–Genetics

0 Followers
 · 
102 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Unraveling the functions of the diverse neural types in any local circuit ultimately requires methods to record from most or all of its cells simultaneously. One promising approach to this goal is fluorescence imaging, but existing methods using laser-scanning microscopy (LSM) are severely limited in their ability to resolve rapid phenomena, like neuronal action potentials, over wide fields. Here we present a microscope that rapidly sections a three-dimensional volume using a thin illumination sheet whose position is rigidly coupled to the objective and aligned with its focal plane. We demonstrate that this approach allows exceptionally low-noise imaging of large neuronal populations at pixel rates at least 100-fold higher than with LSM. Using this microscope, we studied the pheromone-sensing neurons of the mouse vomeronasal organ and found that responses to dilute urine are largely or exclusively restricted to cells in the apical layer, the location of V1r-family-expressing neurons.
    Neuron 04/2008; 57(5):661-72. DOI:10.1016/j.neuron.2008.01.011 · 15.98 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ca2+ currents, especially those activated at low voltages (LVA), influence burst generation in thalamocortical circuitry and enhance the abnormal rhythmicity associated with absence epilepsy. Mutations in several genes for high-voltage-activated (HVA) Ca2+ channel subunits are linked to spike-wave seizure phenotypes in mice; however, none of these mutations are predicted to increase intrinsic membrane excitability or directly enhance LVA currents. We examined biophysical properties of both LVA and HVA Ca2+ currents in thalamic cells of tottering (tg; Cav2.1/alpha1A subunit), lethargic (lh; beta4 subunit), and stargazer (stg; gamma2 subunit) brain slices. We observed 46, 51, and 45% increases in peak current densities of LVA Ca2+ currents evoked at -50 mV from -110 mV in tg, lh, and stg mice, respectively, compared with wild type. The half-maximal voltages for steady-state inactivation of LVA currents were shifted in a depolarized direction by 7.5-13.5 mV in all three mutants, although no alterations in the time-constant for recovery from inactivation of LVA currents were found. HVA peak current densities in tg and stg were increased by 22 and 45%, respectively, and a 5 mV depolarizing shift of the activation curve was observed in lh. Despite elevated LVA amplitudes, no alterations in mRNA expression of the genes mediating T-type subunits, Cav3.1/alpha1G, Cav3.2/alpha1H, or Cav3.3/alpha1I, were detected in the three mutants. Our data demonstrate that mutation of Cav2.1 or regulatory subunit genes increases intrinsic membrane excitability in thalamic neurons by potentiating LVA Ca2+ currents. These alterations increase the probability for abnormal thalamocortical synchronization and absence epilepsy in tg, lh, and stg mice.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2002; 22(15):6362-71. · 6.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Reelin is a positional signal for the lamination of the dentate gyrus. In the reeler mutant lacking Reelin, granule cells are scattered all over the dentate gyrus. We have recently shown that the reeler phenotype of the dentate gyrus can be rescued in vitro by coculturing reeler hippocampal slices with slices from wild-type hippocampus. Here we studied whether Reelin from other brain regions can similarly induce this rescue effect and whether it is mediated via the Reelin receptors apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR). We found that coculturing reeler hippocampal slices with slices from wild-type olfactory bulb, cerebellum, and neocortex rescued the reeler phenotype as seen before with hippocampal slices, provided that the Reelin-synthesizing cells of these regions were placed near the marginal zone of the reeler hippocampal slice. However, coculturing wild-type hippocampal slices with hippocampal slices from mutants deficient in ApoER2 and VLDLR did not rescue the reeler-like phenotype in these cultures. Similarly, no rescue of the reeler-like phenotype was observed in slices from mutants lacking Disabled 1 (Dab1), an adapter protein downstream of Reelin receptors. Conversely, reeler hippocampal slices were rescued by coculturing them with slices from Dab1(-/-) mutants or ApoER2(-/-)/VLDLR(-/-) mice. These findings show that Reelin from other brain regions can substitute for the loss of hippocampal Reelin and that rescue of the reeler phenotype observed in our coculture studies is mediated via lipoprotein receptors for Reelin and Dab1.
    The Journal of Comparative Neurology 03/2006; 495(1):1-9. DOI:10.1002/cne.20846 · 3.51 Impact Factor