Male-specific features are reduced in Mecp2-null mice: analyses of vasopressinergic innervation, pheromone production and social behaviour

Abstract

Deficits in arginine vasopressin (AVP) and oxytocin (OT), two neuropeptides closely implicated in the modulation of social behaviours, have been reported in some early developmental disorders and autism spectrum disorders. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene are associated to Rett syndrome and other neuropsychiatric conditions. Thus, we first analysed AVP and OT expression in the brain of Mecp2-mutant mice by immunohistochemistry. Our results revealed no significant differences in these systems in young adult Mecp2-heterozygous females, as compared to WT littermates. By contrast, we found a significant reduction in the sexually dimorphic, testosterone-dependent, vasopressinergic innervation in several nuclei of the social brain network and oxytocinergic innervation in the lateral habenula of Mecp2-null males, as compared to WT littermates. Analysis of urinary production of pheromones shows that Mecp2-null males lack the testosterone-dependent pheromone darcin, strongly suggesting low levels of androgens in these males. In addition, resident-intruder tests revealed lack of aggressive behaviour in Mecp2-null males and decreased chemoinvestigation of the intruder. By contrast, Mecp2-null males exhibited enhanced social approach, as compared to WT animals, in a 3-chamber social interaction test. In summary, Mecp2-null males, which display internal testicles, display a significant reduction of some male-specific features, such as vasopressinergic innervation within the social brain network, male pheromone production and aggressive behaviour. Thus, atypical social behaviours in Mecp2-null males may be caused, at least in part, by the effect of lack of MeCP2 over sexual differentiation.

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Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AC/ADP:

Nucleus of the anterior commissure/anterodorsal preoptic nucleus region

AcbC:

Nucleus accumbens, core

AcbSh:

Nucleus accumbens, shell

BST:

Bed nucleus of the stria terminalis

BSTMPI:

Bed nucleus of the stria terminalis, medial division, posterointermediate part

Ce:

Central amygdaloid nucleus

dEn:

Dorsal endopiriform cortex

dlPAG:

Dorsolateral periaqueductal grey

DMH:

Dorsomedial hypothalamic nucleus

DR:

Dorsal raphe nucleus

LHb:

Lateral habenular nucleus

LS:

Lateral septum

Me:

Medial amygdaloid nucleus

MeA:

Medial amygdaloid nucleus, anterior part

MePD:

Medial amygdaloid nucleus, posterodorsal part

MHb:

Medial habenular nucleus

Opt:

Optic tract

Pa:

Paraventricular hypothalamic nucleus

Pe:

Periventricular hypothalamic nucleus

SCh:

Suprachiasmatic nucleus

SON:

Supraoptic nucleus

SOR:

Supraoptic nucleus, retrochiasmatic part

St:

Striatum

vHip:

Ventral hippocampus

vlPAG:

Ventrolateral periaqueductal grey

vmStP:

Ventromedial striatopallidum

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Acknowledgements

Authors are indebted to Chelsie Villanueva-Hayes for technical support in the acquisition of pilot data and Dr. Adoración Hernández-Martínez for providing a supplementary figure. Funded by the Spanish Ministry of Economy and Competitiveness (BFU2016-77691-C2-1-P) to FMG, EL and CAP; Conselleria d’Educació, Investigació, Cultura i Esport (PROMETEO/2016/076) and Universitat Jaume I (UJI-B2016-45) to FMG; E-Rare-2 JTC 2012 and E-Rare-2 JTC 2014 by the German Federal Ministry of Education and Research (BMBF) [01GM1302 to M.S., 01GM1505 to O.S.]; Bial Foundation, Grants for Scientific Research, 85/18 to M.S.; and Ayudas FinRett 2019 para la Investigación del Síndrome de Rett to CAP.

Funding

Funded by the Spanish Ministry of Economy and Competitiveness (BFU2016-77691-C2-1-P) to FMG, EL and CAP; Conselleria d’Educació, Investigació, Cultura i Esport (PROMETEO/2016/076) and Universitat Jaume I (UJI-B2016-45) to FMG; E-Rare-2 JTC 2012 and E-Rare-2 JTC 2014 by the German Federal Ministry of Education and Research (BMBF) [01GM1302 to M.S., 01GM1505 to O.S.]; Bial Foundation, Grants for Scientific Research, 85/18 to M.S.; and Ayudas FinRett 2019 para la Investigación del Síndrome de Rett to CAP.

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CAP, MS, FMG and EL designed research. EMR, AMS, EK, AB, FJMM and MS performed research. EMR, AMS, CAP and MS analysed data. EMR, AMS, CAP and MS wrote the paper. EL, FMG and OS discussed the data and the draft of the manuscript. OS provided mice. All authors read and approved the final version of the manuscript. The authors declare no competing interests.

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Correspondence to Mónica Santos or Carmen Agustín-Pavón.

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All the procedures were carried out in strict accordance with the EU directive 2010/63/EU. The protocols were approved by the local veterinary office of the University Otto-von-Guericke and the Animal Experimentation Ethics Committee of the University of Valencia, Protocol 2019/VSC/PEA/0027.

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Martínez-Rodríguez, E., Martín-Sánchez, A., Kul, E. et al. Male-specific features are reduced in Mecp2-null mice: analyses of vasopressinergic innervation, pheromone production and social behaviour. Brain Struct Funct 225, 2219–2238 (2020). https://doi.org/10.1007/s00429-020-02122-6

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Keywords

  • Aggression
  • Autism spectrum disorders
  • Methyl-CpG-binding protein 2
  • Nonapeptides
  • Rett syndrome
  • Social behaviour