Effekte der Cacna1c Haploinsuffizienz auf Sozialverhalten und adulte hippocampale Neurogenese bei Ratten

Genomweite Assoziationsstudien liefern überzeugende Hinweise darauf, dass das Risikogen CACNA1C an der Ätiologie der wichtigsten neuropsychiatrischen Störungen wie Depression, bipolare Störung, Autismus und Schizophrenie beteiligt ist. CACNA1C kodiert die porenformende α1c Untereinheit des spannungs...

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Bibliographic Details
Main Author: Redecker, Tobias Manuel
Contributors: Wöhr, Markus (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2020
Online Access:PDF Full Text
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Genome-wide association studies provide convincing evidence that the risk gene CACNA1C is involved in the etiology of all major neuropsychiatric disorders such as depression, bipolar disorder, autism and schizophrenia. CACNA1C encodes the pore-forming α1c subunit of the voltage-dependent L-type Cav1.2 calcium channel, which plays an important role in regulating neuronal excitability, synaptic plasticity and gene expression by controlling calcium influx into the cell. Neuropsychiatric disorders also show high comorbidity and overlapping symptoms. In particular, deficits in social functioning and alterations of the affective state are prevalent. Interestingly, sex-dependent effects of CACNA1C on the prevalence of neuropsychiatric disorders and psychological characteristics have been reported, as female individuals are more affected by CACNA1C mutations than males. Genetically modified rodent models provide an important translational approach to investigate the fundamental pathomechanisms of neuropsychiatric disorders. Using behavioral studies in Cacna1c mouse and rat models deficits in social behavior and sex-dependent effects on behavioral phenotypes were repeatedly found. In this dissertation, a female haploinsufficient Cacna1c rat model was used to study the impact of Cacna1c on social behavior and communication by 50-kHz ultrasonic vocalizations. The findings of Study I suggest that a partial Cacna1c depletion leads to a reduction in the emission of 50-kHz ultrasonic vocalizations and mild social deficits during direct social interaction of female rats. Taken together this implies a decreased positive affective state. In Cacna1c rodent models, reduced adult hippocampal neurogenesis, which is involved in the pathology of neuropsychiatric disorders, has also been observed along with disorder-like behavioral phenotypes. Therefore, in Study II the effect of Cacna1c on different neurogenesis processes and the brain morphology of female rats was investigated. In contrast to previous studies, which primarily used male animals, no influence of Cacna1c on adult hippocampal neurogenesis and brain morphology of female rats was found. In summary, a partial Cacna1c haploinsufficiency is associated with an reduced positive affective state and mild social deficits in female rats, whereas adult hippocampal neurogenesis and brain anatomy are not affected.