Dokument

Summary:
Mental disorders affect a great number of people worldwide and are highly debilitating. While genetic and environmental influences are thought to contribute to their etiology, the exact mechanisms are still poorly understood. The psychiatric risk gene CACNA1C codes for the α1c subunit of voltage-gated calcium channels and has been associated with major depression, bipolar disorder, schizophrenia and autism spectrum disorders in genome-wide association studies and was further implicated by clinical studies and those using genetically altered mice. In an effort to elucidate how CACNA1C interacts with environmental influences to confer disorder risk, this dissertation used a newly developed constitutive Cacna1c heterozygous rat model to examine male and female animals in paradigms aimed at cognitive abilities and social behavior, both of which frequently found dysfunctional in neuropsychiatric disorders. In Study I and II, sex-specific effects of Cacna1c haploinsufficiency were discovered on rough-and-tumble play, emission of ultrasonic vocalizations (USV) and behavioral reactions in the USV playback paradigm, indicative of altered salience coding for social stimuli and reduced incentive value of pro-social interactions. For Study III, male and female rats were subjected to spatial learning and relearning on the radial arm maze, as well as to novel object recognition. The same paradigms were applied in Study IV, in which animals were previously exposed to four weeks of either post-weaning social isolation, standard housing or social and physical enrichment during the critical juvenile developmental period. Compared to the prominent social deficits in Study I and II, intact spatial and reversal learning abilities were seen in Cacna1c heterozygous animals with initial perseverative tendencies in males. Enrichment had an overall positive effect on learning and cognitive flexibility, whereas social isolation caused a profound impairment in object recognition, regardless of genotype. Furthermore, deficits observed in heterozygous animals under standard housing conditions were rescued by enriched rearing conditions, in the sense of a gene x environment interaction. Together, this dissertation adds to the growing body of evidence suggesting that a variation in Cacna1c genotype is causally involved in social and cognitive dysfunction as core phenotypes of various neuropsychiatric disorders, yet that individuals harboring genetic risk may benefit from early intervention and positive environmental influence.

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