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In utero adversity and later life behavioural disorders: the role of Cdkn1c

McNamara, Gráinne 2014. In utero adversity and later life behavioural disorders: the role of Cdkn1c. PhD Thesis, Cardiff University.
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Abstract

Genes that are imprinted are subject to a developmentally determined epigenetic marking, which restricts expression to a single allele, dependant on the parent of origin. Selection of imprinted genes for monoallelic expression indicates their function is highly dosage sensitive. Altered dosage of imprinted genes has been linked to a number of neurological conditions, including psychosis. Cdkn1c is an example of an imprinted gene whose expression is sensitive to the in utero environment. Considerable development of the nervous system takes place in utero and suboptimal pregnancies have been linked to the occurrence of psychiatric and other behavioural disorders in adults. One mechanism through which the maternal environment may impact foetal development is by altering the epigenetic regulation of vulnerable genes. A prenatal low protein or high fat diet resulted in alterations in a subset of imprinted gene in the brains of the offspring at E18.5. This was accompanied by sexually dimorphic changes in the dopaminergic system. Previously published findings reporting sensitivity of Cdkn1c to a prenatal low protein diet were replicated with a 1.8 fold increase in neural Cdkn1c expression observed. This was shown to be due to a change in the parental contribution to expression levels of this gene. Modelling the specific alteration of an increase in Cdkn1c genetically (Cdkn1cBACx1 line) revealed anhedonia, but with an increased motivational drive, towards a palatable solution, with corresponding changes in the reward system responsivity and chemistry in the adult brain. Additionally presence of a Cdkn1cBACx1 animal in a group destabilised the social hierarchy, negatively effecting fitness of all group members. An adverse inutero environment increases Cdkn1c levels to those reminiscent of the genetic ‘loss of imprinting’ model. Such alteration in expression of Cdkn1c has significant consequences for adult neurochemistry, reward processing and the social environment and fitness of the group. This work suggests a potentially crucial role, of at least Cdkn1c, and perhaps imprinted genes more generally, in mediating the negative consequences of an adverse in utero environment.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > RG Gynecology and obstetrics
Funders: Wellcome Trust
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:52
URI: https://orca.cardiff.ac.uk/id/eprint/69702

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