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Mild expression differences of MECP2 influencing aggressive social behavior.

ABSTRACT: The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (~50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3'UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2 mRNA expression differs in peripheral blood mononuclear cells by ~50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3'UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior.

SUBMITTER: Tantra M

PROVIDER: S-EPMC4023888 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Mild expression differences of MECP2 influencing aggressive social behavior.

Tantra Martesa M Hammer Christian C Kästner Anne A Dahm Liane L Begemann Martin M Bodda Chiranjeevi C Hammerschmidt Kurt K Giegling Ina I Stepniak Beata B Castillo Venzor Aracely A Konte Bettina B Erbaba Begun B Hartmann Annette A Tarami Asieh A Schulz-Schaeffer Walter W Rujescu Dan D Mannan Ashraf U AU Ehrenreich Hannelore H

EMBO molecular medicine 20140501 5

The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (~50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a pheno ...[more]

PMID: 24648499

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Project description:Social rejection elicits profound feelings of distress. From an evolutionary perspective, the best way to alleviate this distress is to behave prosocially, minimizing the likelihood of further exclusion. Yet, examples ranging from the playground to the pub suggest rejection commonly elicits aggression. Opposing theoretical perspectives and discordant empirical results have left a basic question unanswered: does rejection more commonly elicit prosocial or aggressive behavior? We conducted three meta-analyses (one with studies measuring aggressive behavior; one with studies measuring prosocial behavior; and one with studies measuring both aggressive and prosocial behavior; N = 3864) to quantify: (1) the extent to which social rejection elicits prosocial or aggressive behavior and (2) potential moderating effects on these relations. Random-effects models revealed medium effects such that social rejection potentiated aggressive behavior (k = 19; d = 0.41, p < .0001) and attenuated prosocial behavior (k = 7; d = 0.59, p < .0001), an effect that remained consistent even when participants were given the option to behave prosocially or aggressively (k = 15; d = 0.71, p < .0001). These results cast doubt on the theory that rejection triggers prosocial behavior, and instead suggest it is a robust elicitor of aggression. Statement of Relevance: To our knowledge, these meta-analyses are the first to directly test whether social rejection elicits aggressive or prosocial behavior. By including a comprehensive collection of both published and unpublished research studies, and examining a wide variety of previously untested moderators, we show that social rejection robustly elicits aggressive behavior and inhibits prosocial behavior. Additionally, we demonstrate that aggressive behavior following social rejection is not simply a function of limited choices in response options. In fact, aggressive behavior was evoked even when the option to engage in prosocial behavior was provided. Furthermore, we conducted a comprehensive narrative review of the neural mechanisms underlying social rejection-elicited aggressive and prosocial behavior to supplement primary analyses. Overall, we believe that our work makes a critical theoretical contribution to the field.

Project description:Several neurodevelopmental disorders are marked by atypical Methyl-CpG-binding protein 2 (MeCP2) expression or function; however, the role of MeCP2 is complex and not entirely clear. Interestingly, there are sex differences in some of these disorders, and it appears that MeCP2 has sex-specific roles during development. Specifically, recent data indicate that a transient reduction in MeCP2 within developing amygdala reduces juvenile social play behavior in males to female-typical levels. These data suggest that MeCP2 within the amygdala is involved in programming lasting sex differences in social behavior. In the present study, we infused MeCP2 or control siRNA into the amygdala of male and female rats during the first three days of postnatal life in order to assess the impact of a transient reduction in MeCP2 on arginine vasopressin (AVP), a neural marker that is expressed differentially between males and females and is linked to a number of social behaviors. The expression of AVP, as well as several other genes, was measured in two-week old and adult animals. Two-week old males expressed more AVP and galanin mRNA in the amygdala than females, and a transient reduction in MeCP2 eliminated this sex difference by reducing the expression of both gene products in males. A transient reduction in MeCP2 also decreased androgen receptor (AR) mRNA in two-week old males. In adulthood, control males had more AVP-immunoreactive (AVP-ir) cells than females in the centromedial amygdala (CMA), bed nucleus of the stria terminalis (BST) and in the fibers that project from these cells to the lateral septum (LS). A transient reduction in MeCP2 eliminated this sex difference. Interestingly, there were no lasting differences in galanin or AR levels in adulthood. Reducing MeCP2 levels during development did not alter estrogen receptor?, neurofilament or Foxg1. We conclude that a transient reduction in MeCP2 expression in the developing male amygdala has a transient impact on galanin and AR expression but a lasting impact on AVP expression, highlighting the importance of MeCP2 in organizing sex differences in the amygdala.

Dataset Information

Mild expression differences of MECP2 influencing aggressive social behavior.

Publications

Mild expression differences of MECP2 influencing aggressive social behavior.

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