Abstract
Gonadotropin-releasing hormone (GnRH) neurons play a key role in the central regulation of reproduction. In proestrous female mice, estradiol triggers the pre-ovulatory GnRH surge, however, its impact on the expression of neurotransmitter receptor genes in GnRH neurons has not been explored yet. We hypothesized that proestrus is accompanied by substantial changes in the expression profile of genes coding for neurotransmitter receptors in GnRH neurons. We compared the transcriptome of GnRH neurons obtained from intact, proestrous, and metestrous female GnRH-GFP transgenic mice, respectively. About 1500 individual GnRH neurons were sampled from both groups and their transcriptome was analyzed using microarray hybridization and real-time PCR. In this study, changes in mRNA expression of genes involved in neurotransmitter signaling were investigated. Differential gene expression was most apparent in GABA-ergic (Gabbr1, Gabra3, Gabrb3, Gabrb2, Gabrg2), glutamatergic (Gria1, Gria2, Grin1, Grin3a, Grm1, Slc17a6), cholinergic (Chrnb2, Chrm4) and dopaminergic (Drd3, Drd4), adrenergic (Adra1b, Adra2a, Adra2c), adenosinergic (Adora2a, Adora2b), glycinergic (Glra), purinergic (P2rx7), and serotonergic (Htr1b) receptors. In concert with these events, expression of genes in the signaling pathways downstream to the receptors, i.e., G-proteins (Gnai1, Gnai2, Gnas), adenylate-cyclases (Adcy3, Adcy5), protein kinase A (Prkaca, Prkacb) protein kinase C (Prkca) and certain transporters (Slc1a4, Slc17a6, Slc6a17) were also changed. The marked differences found in the expression of genes involved in neurotransmitter signaling of GnRH neurons at pro- and metestrous stages of the ovarian cycle indicate the differential contribution of these neurotransmitter systems to the induction of the pre-ovulatory GnRH surge, the known prerequisite of the subsequent hormonal cascade inducing ovulation.
Highlights
Gonadotropin-releasing hormone (GnRH) neurons play a fundamental role in the maintenance of reproduction (Knobil and Neill, 2006)
GnRH neurons are controlled by different neuronal networks via specific membrane receptors for neurotransmitters and neuropeptides released from the presynaptic neuronal afferents (Smith and Jennes, 2001; Campbell, 2007) that modulate the synthesis rate and release pattern of GnRH and other coproduced neuromodulators (Finn et al, 1998; Christian and Moenter, 2010)
Receptor subunits of GABAergic, glutamatergic, and cholinergic communication, as well as receptors participating in adrenergic, serotonergic, dopaminergic, glycinergic, adenosinergic, and purinergic neurotransmission exhibited significant changes (FC > 1.6; adjusted p < 0.05) in gene expression levels
Summary
Gonadotropin-releasing hormone (GnRH) neurons play a fundamental role in the maintenance of reproduction (Knobil and Neill, 2006). Estradiol (E2) exerts biphasic effects on GnRH neurons and the release of the decapeptide (Sarkar and Fink, 1980; Herbison, 1998). It predominantly suppresses the GnRH system via negative feedback effects with the exception of proestrus when the rising level of E2 primes the system for the preovulatory GnRH surge (Sarkar et al, 1976). In the preovulatory GnRH surge period, GnRH neurons undergo activation exemplified by expression of the immediate early gene c-Fos (Lee et al, 1990), increased transcriptional activity (Chiu et al, 1988; Wang et al, 1995), induction of hormone synthesis (Gore and Roberts, 1997; Finn et al, 1998) and altered firing pattern (Christian et al, 2005; Farkas et al, 2013)
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