Behavioural and Molecular Changes Associated with Advanced Paternal Age

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Epidemiological studies highlight a robust association between advanced paternal age and risk for several neuropsychiatric disorders including autism, schizophrenia and bipolar disorder. In this study a mouse model was used to investigate behavioural and molecular effects of advanced paternal age on the offspring. C57BL/6J females aged 2 months were mated with fathers of the same strain of three different ages: 2 months to represent ’young’ fathers, 10 months to represent ’old’ fathers and 12 months to represent ’very old’ fathers. The offspring were subjected to behavioural tests to investigate their anxiety, locomotion, exploration, memory and social interaction. Significant reductions in exploratory, and particularly social, behaviours in the offspring of old fathers were observed. The deficit in social behaviour is interesting, given that social deficits are a common hallmark across the neuropsychiatric disorders associated with advanced paternal age. -- A variety of methods were utilised to investigate any molecular changes that might underlie the observed paternal age effect. Spermatozoa undergo multiple divisions throughout the male lifespan, potentially leading to a higher incidence of de novo genomic alterations in the offspring. To investigate whether copy number variation (CNV) was associated with advanced paternal age, DNA from the offspring was subjected to genome-wide CNV analysis using comparative genomic hybridisation (CGH) combined with high-resolution microarrays. No differences in the number or size of CNVs or the genes affected by CNVs between the offspring of young fathers and offspring of old fathers were observed. An alternative hypothesis is that epigenetic alterations may explain the relationship between advanced paternal age and behavioural alterations in offspring.
Date of Award2012
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJonathan Mill (Supervisor) & Ian Craig (Supervisor)

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