Dokument

Zusammenfassung:
Die Prävalenz von Autismus-Spektrum-Störungen (ASS) zeigt eine steigende Tendenz. Während im Jahr 2000 in den USA bei einem von 150 achtjährigen Kindern eine ASS diagnostiziert wurde, lag diese Rate im Jahr 2012 bereits bei einem von 68 Kindern. Einhergehend mit dieser Zunahme an Diagnosen lässt sich im Zusammenhang mit einer alternden Bevölkerung ein Trend zugunsten später Vaterschaft finden. Das hohe paternale Alter (HPA) stellt einen unabhängigen Risikofaktor für das Auftreten von ASS beim Nachwuchs dar. Das Verstehen der diesem Risikofaktor zugrundeliegenden Pathomechanismen ist somit aus mehreren Gründen von Interesse. Auf der einen Seite dient das Erforschen dieser Mechanismen einem besseren Verständnis der krankheitsspezifischen Pathogenese von ASS. Auf der anderen Seite tangiert es, bei Fortsetzung beschriebener Trends, auch volkswirtschaftliche Belange und wirft die Frage nach der Notwendigkeit präventionsmedizinischer Maßnahmen auf. Im Rahmen der vorliegenden Arbeit wurde im Tiermodell durch einen Lern-/Umlernversuch im radialen Acht-Arm- Labyrinth der Einfluss des hohen paternalen Alters auf perseverierendes Verhalten, einem Kernsymptom von ASS, untersucht. Darüber hinaus wurde der Einfluss des HPA auf eine mit ASS assoziierte verminderte Gedächtnisleistung geprüft. In Anbetracht der Tatsache, dass Krug et. al. (2014) in einer Humanstudie einen Einfluss des väterlichen Alters auf die Hippocampusgröße zeigen konnten, erfolgte eine morphologische Untersuchung dieser Hirnregion unter Zuhilfenahme histologischer Methoden. Die Untersuchung dieser Hirnregion ist zudem von Interesse, da in früheren Studien eine veränderte Hippocampusmorphologie mit ASS assoziiert wurde. Darüber hinaus wurden die Rattengehirne in der vorliegenden Arbeit bei der Hälfte der Versuchstiere vor und bei der anderen Hälfte nach dem Lern-/ Umlernversuch entnommen. Durch den Vergleich der Gehirne beider Entnahmezeitpunkte konnte ein potentieller Einfluss des Lern-/Umlernversuchs auf die Hippocampusmorphologie untersucht werden. In der vorliegenden Studie führte hohes paternales Alter zu milden kognitiven Defiziten im Sinne einer dezenten Einschränkung des Referenzgedächtnisses während der Umlernphase. Ein perseverierendes Verhalten konnte, ebenso wie weitere Gedächtnisstörungen, nicht beobachtet werden. Im Gegensatz dazu konnte ähnlich den Befunden von Krug et al. (2014) gezeigt werden, dass hohes paternales Alter auch im Tiermodell zu morphologischen Veränderungen hippocampaler Subregionen führt. Interessanterweise zeigte sich bei den Männchen eine Größenreduktion der Subregion CA3 in beiden Hippocampi bei Hirnentnahme vor dem Lern-/Umlernversuch. Im Gegensatz dazu war bei den Weibchen lediglich bei Hirnentnahme im Anschluss an den Lern-/ Umlernversuch eine Größenreduktion der Subregionen CA3, CA1_mol und der Gesamtfläche des rechten Hippocampus zu finden. Dieser Befund legt den Schluss nahe, dass sich der Lern-/Umlernversuch möglichweise im Sinne eines Stressors andersartig auf die Tiere der HPA-Gruppe ausgewirkt haben könnte. Darüber hinaus zeigt sich eine Hemisphären- und geschlechterspezifische Wirkung. Zusammengenommen kommt die vorliegende Studie zu dem Ergebnis, dass hohes paternales Alter zu einer veränderten Hippocampusmorphologie und milden kognitiven Defiziten führt. Da ASS ein sehr heterogenes Krankheitsbild darstellen, welches im Rahmen dieser Studie nur in Teilaspekten untersucht werden konnte, muss in weiterführenden Studien untersucht werden, inwiefern das hohe paternale Alter weitere dem Autismusspektrum zuzuordnende Verhaltensweisen bedingen würde.

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