ESPE Abstracts (2016) 86 P-P1-722

Role of the Metabotropic mGlu5 Glutamate Receptor in the Initiation of Puberty and Reproduction in Female Mice

Ioana Intaa, Roberto De Angelisb, Emese Domonkosc,d, Katja Lankischc, Ulrich Boehmb, Peter Gassc & Markus Bettendorfa

aDivision of Paediatric Endocrinology and Diabetes, University Children’s Hospital, Heidelberg, Germany; bDepartment of Pharmacology and Toxicology, University of Saarland School of Medicine, Homburg, Germany; cRG Animal Models in Psychiatry, Central Institute of Mental Health, Mannheim, Germany; dInstitute of Molecular Biomedicine, Faculty of Medicine, Bratislava, Slovakia

Background: The neuroendocrine mechanisms of the initiation of puberty are still incompletely deciphered. Accumulating data indicate a main role of the glutamate system in regulating hypothalamic GnRH. However, the underlying neurobiological mechanisms are yet poorly investigated. Mice lacking metabotropic mGlu5 receptors (mGluR5) show sever unexplained infertility.

Objective and hypotheses: We aimed in the present study to analyze the specific role of mGluR5 in the initiation of puberty and reproduction in mice.

Method: Sexual maturation of mGluR5 knockout (KO) and wildtype littermates was investigated by recording in vivo vaginal opening (VO) and estrous cycles (using vaginal smears) and uterine weight after sacrifice. Further we investigated the reproductive performance (total number of pups born per female) and serum gonadotropin hormone (assessed by magnetic bead immunoassay) in mGluR5 KO and wildtype females. All experiments were approved by the German Committee on Animal Care.

Results: mGluR5 KO mice showed markedly delayed puberty, as determined by time of VO (32.54 ± 0.57 days in mGluR5 −/− mice, n=13; 29.76 ± 0.55 days in wildtype mice, n=29, P<0.05), first estrus (52.4 ± 1.47 days in mGluR5 −/− mice, n=5; 34.5 ± 2.23 days in wildtype, n=6, P<0.001) and uterus weight (7.63 ± 0.58 mg in mGluR5 −/− mice, n=8; 14.13 ± 1.45 g in wildtype mice, n=7, P<0.001). Additionally, significant decrease in serum levels of follicle-stimulating hormone (FSH, 232.09 ± 26.37 pg/ml, n=9 in wildtype female, 134.91 ± 11.08 in mGluR5 −/− female, n=8, P<0.01) and reduced reproductive performance (0.11 ± 0.11 pups/female mGluR5 −/− mice, n=9; 7.79 ± 0.38 in wildtype mice, n=19, P<0.001) were recorded.

Conclusion: These results suggest an important role of mGluR5 in the modulation of puberty onset and fertility. Our data support future research on the role of this glutamate receptor in the GnRH-mediated gonadotropin secretion and its impact on puberty and fertility.

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