Prenatal Maternal Immune Activation Causes Postnatal Epigenetic Differences in the Adolescent Mouse Brain

Friday, May 16, 2014: 11:42 AM
Marquis A (Marriott Marquis Atlanta)
B. Paul1, Q. Li1, E. L. Dempster2, C. Wong2, P. C. Sham1,3, J. Mill2,4 and G. M. McAlonan1,5, (1)Department of Psychiatry, The University of Hong Kong, Hong Kong, Hong Kong, (2)MRC SGDP Centre, Institute of Psychiatry, King's College London, London, United Kingdom, (3)Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, Hong Kong, (4)University of Exeter Medical School, Exeter University, Exeter, United Kingdom, (5)Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, King’s College London, London, United Kingdom
Background: Epigenetic changes such as DNA cytosine methylation modulate gene function across brain and are implicated in the pathophysiology of neurodevelopmental disorders such as autism. Epigenetic changes can be caused by environmental exposures such as inflammation, and may at least partly explain why prenatal exposure to inflammation increases the risk of neurodevelopmental disorders. Our group and others have shown that mice exposed to maternal inflammation prenatally have structural abnormalities in the brain and behaviour abnormalities which are analogous to those found in autism and related conditions such as schizophrenia. The current study tested the hypothesis that prenatal inflammation alters DNA methylation in key brain regions linked to autism. These were, the striatum, linked to flexibility and repetitive behaviours in autism; and the hypothalamus, an endocrine regulatory centre which synthesizes key hormones linked to autism, namely oxytocin and vasopressin. We also carried out a pilot investigation of the methylation state of the Mecp2 gene as it has widespread gene regulatory function and, in addition to its established role in the pervasive developmental condition Rett’s syndrome, its polymorphism has been linked to autism.

Objectives:  To examine the epigenetic changes in the adolescent brain associated with prenatal inflammation.

Methods:  We harvested brain tissue from 6 week old offspring of mice exposed to the viral analogue PolyI:C or saline on gestation day 9. We used EpiTYPER assay (Sequenom) to quantitatively analyze differences in CpG methylation of Long Interspersed Elements-1 (LINE1 or L1) as a proxy of global methylation. We also quantified CpG methylation of Mecp2 promoter region using the same method.

Results: Prenatal exposure to PolyI:C did not alter global DNA methylation in striatum but caused significant hypomethylation in the hypothalamus compared to saline controls (t = 2.44, P = 0.019). There was also significant hypomethylation of the promoter region of Methyl CpG Binding Protien2 (Mecp2) (t = 3.32, P = 0.002) in the hypothalamus in offspring exposed to PolyI:C (PolyI:C mean 26.57%, saline mean 34.63%).

Conclusions:  These results provide direct experimental evidence that exposure to inflammation during prenatal life causes widespread epigenetic changes which include Mecp2 promoter methylation. They also suggest that environmental and genetic risk factors associated with neurodevelopmental disorders such as autism act upon similar pathways.