ESPE Abstracts (2016) 86 FC12.1

Rabconnectin3-[alpha] is Indispensable for the Activation and Maturation of the GnRH Neuronal Network

Brooke Tataa,b, Carole Harbulota, Zsolt Csabaa, Sandrine Jacquiera & Nicolas de Rouxa,c

aHopital Robert Debré, Inserm U1141, Paris, France; bInserm U1172, Lille, France; cParis Diderot University-Bio Sorbonne Cité, Paris, France

Background: Acquisition and maintenance of fertility in mammals rely on the function of Gonadotropin Releasing Hormone (GnRH) neurons. During the juvenile period, GnRH neurons undergo morphological maturation, which involves changes in synaptic inputs and neuropeptide activation from afferent neurons. The functional importance of this maturation could be a pre-requisite for puberty onset. However, the mechanisms behind these dynamic changes have yet to be identified.

Objective and hypotheses: Previously, we found that the neuronal knock-down of Dmxl2, encoding for the synaptic protein rabconnectin3-α (rbcn3-α), reproduced in mice (nes::cre;Dmxl2loxp/wt) the GnRH deficiency found in DMXL2 mutated patients. Here, we aimed to clarify if the GnRH deficiency observed in nes::cre;Dmxl2loxp/wt mice was due to abnormal GnRH neuronal maturation.

Method: Kp-10 and E2 injections combined with cre-dependent adenoviral filling of GnRH neurons in vivo in nes::cre;Dmxl2loxp/wt and GnRH::Cre;Dmxl2 knock out mice were used to assess GnRH neuron number, morphology, and activation.

Results: Male nes::cre;Dmxl2loxp/wt mice fail to respond to the GnRH secretagogue, kisspeptin(Kp-10). In adulthood, GnRH neurons display a majority of immature GnRH neuron morphology in both males and female nes::cre;Dmxl2loxp/wt mice. In addition, female nes::cre;Dmxl2loxp/wt mice exhibit an abnormal ovulatory circadian timed LH surge and unable to elicit E2 positive feedback. Important, immature GnRH morphologies in nes::cre;Dmxl2loxp/wt mice were unresponsive to Kp-10 and E2 treatments, but not in GnRH::Cre;Dmxl2 KO mice.

Conclusion: This study reveals that rbcn3-α is required for the maturation and activation of GnRH neurons by afferent neurons. This is a new mechanism of normosmic hypogonadotropic hypogonadism.

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