ESPE Abstracts (2015) 84 P-1-118

Specific Hypothalamic Activation Pattern by mGlu5 Receptor Blockade in vivo During Pubertal Development in Female Mice

Ioana Intaa, Roberto de Angelisb, Katja Lankischc, Christof Dormannc, Natascha Pfeifferc, Ulrich Boehmb, Peter Gassc & Markus Bettendorfa


aUniversity Children’s Hospital Heidelberg, Heidelberg, Germany; bSchool of Medicine, University of Saarland, Homburg, Germany; cMedical Faculty Mannheim, Central Institute of Mental Health, Mannheim, Germany


Background: Puberty is characterised by important changes of brain networks. The glutamate system plays a main role in modulating the onset of puberty as shown for NMDA receptor agonists. However, the underlying mechanisms are poorly understood. Metabotropic mGlu5 receptors (mGluR5) are tightly linked to NMDA receptors. The effect of mGluR5 blockade on neurohormonal mechanisms in puberty initiation were not studied yet.

Objective and hypotheses: To investigate the role of pharmacological blockade of mGluR5 on neuronal activation during puberty in order to identify neuroendocrine signals involved in gonadarche and pubertal progression.

Method: We used profiling of the expression of the immediate early gene c-fos, as marker of neuronal activity, triggered by the selective mGluR5 antagonist 2-Methyl-6-(phenylethynyl)pyridine (MPEP). Female mice at postnatal day (P) 16 to 40 (n=4-6) were treated i.p. with 30 mg/kg MPEP. Coronal brain sections (50 μm) were obtained and c-fos immunohistochemistry was performed. Serum levels of LH and FSH were measured in P26 female mice (n=5) after 7 days of MPEP or normal saline treatment by non-magnetic bead immunoassay. Mice growth, weight and uterus weight were analysed.

Results: We found a remarkably specific activation of the paraventricular nucleus of the hypothalamus (PVNH) by MPEP, starting at P16 and continuing throughout puberty (P16–P40). MPEP reduced LH and FSH levels (pg/ml) as compared to normal saline (LH 38.43±7.65–26.68±4.18, for FSH 119.08±45.66–86.38±17.45).

Conclusion: Our data provide new insights into the role of mGluR5 in pubertal development of female mice. Chronic MPEP treatment reduced LH and FSH levels. MPEP administration activates c-fos specific in the PVNH a key regulator of the hypothalamic-pituitary-adrenal (HPA) axis. Our data support a role of mGluR5 in regulating glutamatergic control of the hypothalamic-pituitary-gonadal (HPG) axis probably by early activation of collateral glutamatergic neurons.

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