Article

Intrinsische Plastizität nach Status Epilepticus durch Regulation spannungsabhängiger Ionenkanäle

Zeitschrift für Epileptologie 01/2003; 16(3):243-249. DOI: 10.1007/s10309-003-0030-8

ABSTRACT Temporallappenepilepsie (TLE) ist eine hufige Unterform
der Epilepsien, die durch wiederholte, aus den mittleren
Anteilen des Schlfenlappens hervorgehende Krampfanflle
gekennzeichnet ist. Im Hippokampus sind eine Vielzahl
molekularer und zellulrer Vernderungen mit der Entwicklung
chronischer Epilepsie vergesellschaftet. Eine vor lngerer Zeit
aufgestellte Hypothese erklrt erhhte Erregbarkeit durch eine
vermehrte Neigung von Nervenzellen im epileptischen Fokus,
spontan oder nach synaptischer Reizung hochfrequente Salven von
Aktionspotenzialen (bursts) zu generieren ("epileptisches
Neuron"). Ein Vielzahl anderer Studien untersttzt die Bedeutung
vernderter synaptischer Konnektivitt zwischen Nervenzellen fr
die Entwicklung eines epileptogenen Fokus ("epileptisches
Netzwerk"). Obwohl sich diese beiden Erklrungsmodelle
gegenseitig nicht ausschlieen, haben sich die meisten
Untersuchungen bisher auf die Analyse vernderter synaptischer
Eigenschaften im epileptogenen Fokus konzentriert. Die
Mglichkeit, dass einzelne Neurone durch Vernderung ihrer
intrinsischen Eigenschaften zu erhhter Erregbarkeit beitragen
knnten, ist dagegen nicht untersucht worden.Wir haben letztere Frage in einem experimentellen
Tiermodell fr TLE untersucht. Wir konnten zeigen, dass die
vernderte Expression spannungsabhngiger Ionenleitfhigkeiten
in der Zellmembran von hippokampalen Nervenzellen die
Entladungseigenschaften von hippokampalen Nervenzellen in der
CA1-Region tiefgreifend verndert. Der Mechanismus des
vernderten Entladungsverhaltens ist vermutlich eine
Hochregulation der Dichte von niederschwellig aktivierbaren
Ca2+-Kanlen, vermittelt durch
Cav 3.2-Untereinheiten. Das vernderte
Entladungsverhalten hat eine langanhaltende Steigerung des
Eingangs-Ausgangs-Verhaltens dieser Neurone bei synaptischer
Reizung zur Folge. Zustzlich legen unsere Resultate nahe, dass
diese Vernderungen intrinsischen Entladungsverhaltens eine
Rolle bei der Initiierung von Krampfanfllen spielen.Zusammenfassend finden bei Epilepsie im epileptogenen
Fokus sowohl Vernderungen der intrinsischen neuronalen
Erregbarkeit als auch der erregenden und hemmenden synaptischen
Konnektivitt statt. Beide Gruppen von Vernderungen knnen zur
erhhten Neigung mesialer temporaler Strukturen, Krampfaktivitt
zu generieren, beitragen. Das Verstndnis sowohl intrinsischer
wie auch synaptischer pathogenetisch relevanter Vernderungen
ist von groer Bedeutung fr die Entwicklung neuer
medikamentser Therapiestrategien.While a multitude of studies have dissected
epilepsy-related changes in synaptic communication between
neurons, alterations in intrinsic firing properties and their
cellular mechanisms have received only minor attention.Here we summarize findings suggesting that intrinsic
properties of hippocampal neurons may be dramatically modified
during epileptogenesis. We have recently shown that CA1
pyramidal neurons in epileptic tissue show an increased
propensity to generate intrinsic burst discharges that most
probably rely on altered voltage-dependent
Ca2+ channels (VDCCs). Our further
experiments suggest that the mechanism underlying increased
Ca2+-dependent bursting is the
up-regulation of a T-type Ca2+
channel in CA1 neurons, most probably mediated by the
Cav 3.2 subunit. The change in intrinsic
properties strongly augment the input-output properties of CA1
neurons to synaptic stimulation. Furthermore, several lines of
evidence indicated that these bursting neurons may be important
for initiation of seizures.Investigating the up-regulation of specific VDCC subtypes
in experimental and human TLE will further our understanding of
the molecular mechanisms involved in the initiation of seizures
in this disorder. It is hoped that such an understanding will
trigger the design of novel antiepileptic drugs specifically
targeted to pathologically altered VDCCs, which might be
effective in the treatment of currently refractory TLE.

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