Modeling neuropsychiatric phenotypes in mice in the frame of translational neuroscience

by Martesa Tantra
Doctoral thesis
Date of Examination:2013-09-17
Date of issue:2014-01-20
Advisor:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Prof. Dr. Nils Brose
Referee:Prof. Dr. Thomas A. Bayer
Persistent Address: http://dx.doi.org/10.53846/goediss-4178

 

 

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Abstract

English

Neuropsychiatric disorders, such as autism spectrum disorders (ASD), schizophrenia, anxiety disorders, major depression and substance use disorders are highly prevalent and contribute to disease burden worldwide. Accumulating evidence consistently suggest neuropsychiatric conditions as results of complex interactions between multiple genetic factors and environmental factors. However, despite large research efforts, the exact neurobiological mechanisms of neuropsychiatric disorders remain largely unknown. The present cumulative thesis has been prepared on the basis of a translational neuroscience approach based on schizophrenic patients of the GRAS (Göttingen Research Association for Schizophrenia) data collection (Ribbe, Friedrichs et al. 2010): translating the findings from basic research using animal models back to human, and vice versa to reveal the relevance of behavioral characterization of genetic mouse models of complex human behavioral disorders, such as psychiatric diseases. Using behavioral genetics to characterize mouse models of complex human behavioral disorders, the role of MECP2 and BAIAP3 genotypes and their common variants in modulating behavioral phenotypes was identified. Within the first paper, BAIAP3/Baiap3 was identified as a genetic factor that modulates anxiety and the response to benzodiazepines in mouse and man (Wojcik, Tantra, Stepniak et al. 2013). The second paper focuses on an elevated seizure propensity as the phenotypical consequences of mildly overexpressing the transcriptional regulator Mecp2 at ~1.5fold wild-type level (Bodda, Tantra et al. 2013). The third publication expanding the results published in the second paper, reveals that subtle alterations in the expression level of Mecp2/MECP2 influence social, particularly aggressive behavior (Tantra, Hammer, Kästner et al. submitted). Overall, this thesis shows the practical implications of behavioral studies of transgenic mice with an elaborate behavioral repertoire that can be used to model phenotypes of complex human behavioral disorders. Behavioral characterizations of these mice gave aid to identify behavioral domains targeted by the genetic variations of the genes of interest, revealing the probable functional role of the genes within the frame of complex human behavioral disorders. The validity of the genetic mouse models described here was further increased by addressing the relevance of the findings in a schizophrenic (GRAS) population.
Keywords: Behavioral neuroscience; Mouse model; behavioral genetics; Phenotyping; Neuropsychiatric disorders
 
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