Dopaminergic and behavioural changes in a loss-of-imprinting model of Cdkn1c

Abstract

The imprinted gene Cdkn1c is expressed exclusively from the maternally inherited allele as a consequences of epigenetic regulation. Cdkn1c exemplifies many of the functional characteristics of imprinted genes, playing a role in foetal growth and placental development. However, Cdkn1c also plays an important role in the brain, being key to the appropriate proliferation and differentiation of midbrain dopaminergic neurons. Using a transgenic model (Cdkn1c^BACx1 ) with a twofold elevation in Cdkn1c expression that mimics loss-of-imprinting, we show that increased expression of Cdkn1c in the brain gives rise to neurobiological and behavioural changes indicative of a functionally altered dopaminergic system. Cdkn1c^BACX1 mice displayed altered expression of dopamine system-related genes, increased tyrosine hydroxylase (Th) staining and increased tissue content of dopamine in the striatum. In addition, Cdkn1c^BACx1 animals were hypersensitive to amphetamine as showed by c-fos expression in the nucleus accumbens. Cdkn1c^BACX1 mice had significant changes in behaviours that are dependent on the mesolimbic dopaminergic system. Specifically, increased motivation for palatable food stuffs, as indexed on a progressive ratio task. In addition, Cdkn1c^BACX1 mice displayed enhanced social dominance. These data show, for the first time, the consequence of elevated Cdkn1c expression on dopamine-related behaviours highlighting the importance of correct dosage of this imprinted gene in the brain. This work has significant relevance for deepening our understanding of the epigenetic factors that can shape neurobiology and behaviour.

Keywords: Dopamine; epigenetics; imprinted genes; p57kip2; reward; social dominance.