Hohes paternales Alter als Risikofaktor für Autismus-Spektrum-Störungen des Nachwuchses: Effekte auf Lern-/Umlernverhalten und Hippocampusmorphologie im Tiermodell der Ratte

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 sic...

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Bibliographic Details
Main Author: Eggebrecht, Julius Caspar
Contributors: Krug, Axel (Prof.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2017
Online Access:PDF Full Text
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The prevalence of autism spectrum disorder (ASD) is increasing. While there was one out of 150 8-year old US-children diagnosed with ASD in 2000, this number has risen to one out of 68 in 2012. Furthermore, there is an ageing society, which is going along with a worldwide trend that fathers are getting older at the time of procreation. High paternal age (HPA) is considered a risk factor for the development of ASD in the offspring. According to that fact, the understanding of underlying causality is of different interest. On the one hand it is supposed to be helpful in the progress of understanding the pathophysiology that leads to ASD, on the other hand it might be of particular interest for prospective Public Health policies. Moreover, it raises the question of whether there is a need for new concepts in Preventive Medicine. Since experimental evidence in humans is not feasible, the development of animal models is needed, allowing for environmental confounders to be controlled. Therefore, a rat model was developed to compare offspring from young and old fathers in learning and reversal learning behaviour using an eight-arm-radial maze. This design also allows testing for perseverative behaviour as a core symptom of ASD. Moreover, it provides the opportunity to look for implicit memory functions that are associated with ASD. Due to the fact that Krug et al. (2014) showed an association between HPA and the volume of the hippocampus in humans, the size of this brain region was investigated using histological methods in the rat model. In addition, the hippocampus is of high interest since altered hippocampal morphology is implicated in ASD. Furthermore, one half of the rat brains were extracted before and the other half shortly after testing the rodents in the radial maze. This design allowed for the analysis of whether experimental training had a potential influence on brain morphology. In this study, it could be shown that HPA leads to mild cognitive impairments in terms of slightly decreased implicit reference memory function during the reversal learning phase. However, there was no evidence of perseveration and further memory dysfunction e.g. working memory errors. In contrast to the minor effect on behaviour and memory, HPA causes morphological alterations of the hippocampus. Interestingly, the influence differed with respect to sex and hemisphere. More precisely, male rats showed a decrease of subregion CA3 in both hippocampi when brains were extracted before the experiment was started. In contrast to these findings, subregion CA1_mol, CA3 and the overall area of the right hippocampus of female rats were reduced in size when brains were extracted shortly after the experiment. These findings suggest that the experiment had a differential impact as a stressor on hippocampal morphology in both groups. Taken together, one can conclude that HPA causes alterations of hippocampal morphology and leads to slight cognitive deficits. However, taking into account the fact that ASD is a very heterogeneous disorder with only a small subset of its symptoms were analysed, further studies need to be conducted to assess whether HPA might cause additional ASD related symptoms.