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Early life adversity and serotonin transporter gene variation interact to affect DNA methylation of the corticotropin-releasing factor gene promoter region in the adult rat brain

Published online by Cambridge University Press:  02 February 2015

Rick H. A. van der Doelen ,
Ilse A. Arnoldussen ,
Hussein Ghareh ,
Liselot van Och ,
Judith R. Homberg  and
Tamás Kozicz
Rick H. A. van der Doelen*
Affiliation:
Radboud University Nijmegen Medical Centre
Ilse A. Arnoldussen
Affiliation:
Radboud University Nijmegen Medical Centre
Hussein Ghareh
Affiliation:
Radboud University Nijmegen Medical Centre
Liselot van Och
Affiliation:
Radboud University Nijmegen Medical Centre
Judith R. Homberg
Affiliation:
Radboud University Nijmegen Medical Centre
Tamás Kozicz
Affiliation:
Radboud University Nijmegen Medical Centre
*
Address correspondence and reprint requests to: Rick H.A. van der Doelen, Radboud University Nijmegen Medical Centre, Geert Grooteplein 21 (route 126), 6525 EZ Nijmegen, The Netherlands; E-mail: rick.vanderdoelen@radboudumc.nl.
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Abstract

The interaction between childhood maltreatment and the serotonin transporter (5-HTT) gene linked polymorphic region has been associated with increased risk to develop major depression. This Gene × Environment interaction has furthermore been linked with increased levels of anxiety and glucocorticoid release upon exposure to stress. Both endophenotypes are regulated by the neuropeptide corticotropin-releasing factor (CRF) or hormone, which is expressed by the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the central amygdala (CeA). Therefore, we hypothesized that altered regulation of the expression of CRF in these areas represents a major neurobiological mechanism underlying the interaction of early life stress and 5-HTT gene variation. The programming of gene transcription by Gene × Environment interactions has been proposed to involve epigenetic mechanisms such as DNA methylation. In this study, we report that early life stress and 5-HTT genotype interact to affect DNA methylation of the Crf gene promoter in the CeA of adult male rats. Furthermore, we found that DNA methylation of a specific site in the Crf promoter significantly correlated with CRF mRNA levels in the CeA. Moreover, CeA CRF mRNA levels correlated with stress coping behavior in a learned helplessness paradigm. Together, our findings warrant further investigation of the link of Crf promoter methylation and CRF expression in the CeA with behavioral changes that are relevant for psychopathology.

Type
Special Section Articles
Information
Development and Psychopathology , Volume 27 , Issue 1: What Works for Whom? Genetic Moderation of Intervention Efficacy , February 2015 , pp. 123 - 135
Copyright
Copyright © Cambridge University Press 2015 

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