Aberrante Konnektivität im humanen epileptischen Hippokampus

Zusammenfassung

Einleitung: Neuronale Netzwerkreorganisationen können zur Epileptogenese der humanen limbischen Epilepsie beitragen. Neben dem aberranten Sprossen von Moosfasern ist dabei eine ausgedehntere Ausprägung von aberranten Faserverbindungen in der Hippokampusformation vorstellbar. Wir untersuchten daher Sprossungsphänomene in der CA1-Region, da dieses Segment in der Temporallappenepilepsie des Menschen am meisten geschädigt ist. Methodik: Akute Hirnschnitte von operativ entfernten Hippokampi (n = 54) von Patienten mit einer pharmakoresistenten Temporallappenepilepsie oder läsionsassoziierten temporomesialen Erkrankungen wurden mit dextranaminkonjugierten Fluoreszenzfarbstoffen markiert und die Faserverbindungen des Hippokampus in transversaler Ebene untersucht. Zur Beurteilung des Moosfasersystems diente zusätzlich die Timm-Färbung. Ergebnisse: Der Nervenzellverlust der resezierten Hippokampi wurde nach dem Wyler-Grading eingeteilt in Non-AHS (keine Ammonshornsklerose), moderate AHS und schwere AHS. Im Gyrus dentatus fand sich in allen Formen der AHS ein unterschiedlich intensives aberrantes Sprossen von Moosfasern, nachweisbar durch fluoreszenzmarkierte Fasern und eine Zinkausfällung in der Molekularschicht des Gyrus dentatus. In der CA1-Region kam es insbesondere in der moderaten Form der AHS zu einer erhöhten Konnektivität zwischen den Projektionsneuronen, während in den Abschnitten vollständigen Zellverlusts Faserverbindungen ungenügend dargestellt waren. In der CA1-Region von Non-AHS-Gewebe fand sich keine aberrante neuronale Verschaltung zwischen den Pyramidenzellen. Schlussfolgerungen: Der Umbau des neuronalen Netzwerkes in der CA1-Region und im Gyrus dentatus weist auf eine weitergehende axonale Reorganisation in den Hauptbereichen der chronisch epileptischen temporomesialen Region hin. Die strukturellen Veränderungen können zu einer Verstärkung von Feedback-Schleifen innerhalb des Hippokampus führen mit der Konsequenz, dass synchrone pathologische Entladungen im Hippokampus befördert werden.

Abstract

Introduction: Remodeling of the neuronal network is one factor for epileptogenesis in human temporal lobe epilepsy. Aberrant sprouting of mossy fibres is a well accepted phenomenon; however, a more widespread rearrangement of fibres in the hippocampal formation is conceivable. We studied whether sprouting occurs in area CA1, as this segment is badly damaged in mesiotemporal sclerosis. Materials and methods: Acute brain slices of hippocampi removed from patients with intractable epilepsy or temporal lesions were labelled with fluorescent dextran-amines. The connectivity of neurons was traced in transverse plains of the hippocampus. Timm staining for zinc in mossy fibres was additionally employed. Results: The nerve cell loss was graded into non-AHS (Ammon's Horn sclerosis), moderate and severe AHS according to the system proposed by Wyler. In the dentate gyrus, mossy fibre sprouting was found in all forms of AHS with varying intensity by showing zinc accumulation and fluorescence labelled mossy fibres in the molecular layer of the dentate gyrus. In area CA1 an increased connectivity between pyramidal cells was found particularly in the moderate form of AHS. In severe cell loss no fibres were present. In non-AHS tissue no increased CA1-CA1 connectivity was found. Conclusions: The rearrangement of the neuronal network in area CA1 and in the dentate gyrus indicates a more widespread axonal reorganisation in the main areas of the chronic epileptic hippocampus. The structural alterations might cause an enhancement of the feed-back loops within the hippocampus with the consequence, that synchronised pathological discharges might be promoted.

Key words

Neuronal connectivity - human temporal lobe epilepsy - hippocampus - dentate gyrus - dextran-amine

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