The scaffold protein p140Cap controls female fertility in mice, acting on the glutamatergic stimulation of GnRH neurons

p140Cap, encoded by SRCIN1 (SRC kinase signaling inhibitor 1), is a scaffold protein participating in several pre- and post-synaptic mechanisms. Since p140Cap KO female mice show hypofertility and delayed puberty onset, we investigated the role of p140Cap in the activity of the hypothalamic gonadotropic system. Migration of Gonadotropin-Releasing Hormone (GnRH) neurons in p140Cap KO embryos appeared normal, and young p140Cap KO animals showed a normal number of GnRH neurons. In contrast, adult p140Cap KO mice showed a significant loss of GnRH neurons and a decreased density of GnRH+ projections in the median eminence (ME), accompanied by reduced levels of GnRH and luteinizing hormone (LH) mRNAs in the hypothalamus and hypophysis, respectively. p140Cap KO mice showed no alteration in the number of kisspeptin (KP) neurons in the anteroventral periventricular nucleus (AVPV), KP+ fibers in the arcuate nucleus (ARC), KP+ punctae on GnRH neurons, and in the responsiveness to exogenous KP in vivo, thus excluding a cell-autonomous defect of GnRH neurons at the level of KP receptor or its signal transduction. Since glutamatergic signaling in the hypothalamus is critical for both puberty onset and modulation of GnRH secretion, we examined the density of glutamatergic synapses in p140Cap KO mice, and we observed a significant reduction in the density of VGLUT+ punctae both globally in the hypothalamus and on GnRH neurons. Our data suggest that the glutamatergic circuitry in the hypothalamus is altered in the absence of p140Cap, and is required for female fertility, independently from the KP system.