scholarly journals Lack of sex differences in gonadotropin-releasing hormone (GnRH) neuron potassium currents and excitability

2021 ◽  
Author(s):  
R Anthony DeFazio ◽  
Suzanne M Moenter
Keyword(s):  
Action Potential ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Brain Slices ◽  
Potassium Currents ◽  
Gonadotropin Releasing Hormone ◽  
Releasing Hormone ◽  
Voltage Gated ◽  
Gnrh Neurons ◽  
Gnrh Release

Gonadotropin-releasing hormone (GnRH) drives pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone, which in turn regulate gonadal functions including steroidogenesis. The pattern of GnRH release and thus fertility depend on gonadal steroid feedback. Under homeostatic (negative) feedback conditions, removal of the gonads from either females or males increases the amplitude and frequency of GnRH release and alters the long-term firing pattern of these neurons in brain slices. The neurobiological mechanisms intrinsic to GnRH neurons that are altered by homeostatic feedback are not well studied and have not been compared between sexes. During estradiol positive feedback, which is unique to females, there are correlated changes in voltage-gated potassium currents and neuronal excitability. We thus hypothesized these same mechanisms would be engaged in homeostatic negative feedback. Voltage-gated potassium channels play a direct role in setting excitability and action potential properties. Whole-cell patch-clamp recordings of GFP-identified GnRH neurons in brain slices from sham-operated and castrated adult female and male mice were made to assess fast (IA) and slow (IK) inactivating potassium currents as well as action potential properties. Surprisingly, no changes were observed in most potassium current properties, input resistance or capacitance and this was reflected in a lack of differences in excitability and specific action potential properties. These results support the concept that, in contrast to positive feedback, steroid negative feedback regulation of GnRH neurons in both sexes is likely conveyed to GnRH neurons via mechanisms that do not induce major changes in the biophysical properties of these cells.

scholarly journals Firing patterns of gonadotropin-releasing hormone neurons are sculpted by their biologic state

2020 ◽  
Vol 7 (8) ◽  
pp. 201040
Author(s):  
Jonathon Penix ◽  
R. Anthony DeFazio ◽  
Eden A. Dulka ◽  
Santiago Schnell ◽  
Suzanne M. Moenter
Keyword(s):  
Action Potential ◽  
Polycystic Ovary ◽  
Brain Slices ◽  
Gonadotropin Releasing Hormone ◽  
Neuron Activity ◽  
Interval Order ◽  
Short Term ◽  
Firing Patterns ◽  
Releasing Hormone ◽  
Gnrh Neurons

Gonadotropin-releasing hormone (GnRH) neurons form the final pathway for the central neuronal control of fertility. GnRH is released in pulses that vary in frequency in females, helping drive hormonal changes of the reproductive cycle. In the common fertility disorder polycystic ovary syndrome (PCOS), persistent high-frequency hormone release is associated with disrupted cycles. We investigated long- and short-term action potential patterns of GnRH neurons in brain slices before and after puberty in female control and prenatally androgenized (PNA) mice, which mimic aspects of PCOS. A Monte Carlo (MC) approach was used to randomize action potential interval order. Dataset distributions were analysed to assess (i) if organization persists in GnRH neuron activity in vitro , and (ii) to determine if any organization changes with development and/or PNA treatment. GnRH neurons in adult control, but not PNA, mice produce long-term patterns different from MC distributions. Short-term patterns differ from MC distributions before puberty but become absorbed into the distributions with maturation, and the distributions narrow. These maturational changes are blunted by PNA treatment. Firing patterns of GnRH neurons in brain slices thus maintain organization dictated at least in part by the biologic status of the source and are disrupted in models of disease.

scholarly journals Kisspeptin Increases γ-Aminobutyric Acidergic and Glutamatergic Transmission Directly to Gonadotropin-Releasing Hormone Neurons in an Estradiol-Dependent Manner

Endocrinology ◽  
2010 ◽  
Vol 151 (1) ◽  
pp. 291-300 ◽  
Author(s):  
Justyna Pielecka-Fortuna ◽  
Suzanne M. Moenter
Keyword(s):  
Negative Feedback ◽  
Positive Feedback ◽  
Brain Slices ◽  
Cell Voltage ◽  
Dependent Manner ◽  
Glutamatergic Transmission ◽  
Neuron Response ◽  
Gnrh Neurons ◽  
Gnrh Release ◽  
In Cells

Abstract GnRH neurons are the final central pathway controlling fertility. Kisspeptin potently activates GnRH release via G protein-coupled receptor 54 (GPR54). GnRH neurons express GPR54, and kisspeptin can act directly; however, GPR54 is broadly expressed, suggesting indirect actions are possible. Transsynaptic mechanisms are involved in estradiol-induced potentiation of GnRH neuron response to kisspeptin. To investigate these mechanisms, separate whole-cell voltage-clamp recordings were performed of γ-aminobutyric acid (GABA)-ergic and glutamatergic transmission to GnRH neurons in brain slices before and during kisspeptin treatment. To determine whether estradiol alters the effect of kisspeptin on synaptic transmission, mice were ovariectomized and either left with no further treatment (OVX) or treated with estradiol implants (OVX+E). Cells were first studied in the morning when estradiol exerts negative feedback. Kisspeptin increased frequency and amplitude of GABAergic postsynaptic currents (PSCs) in GnRH neurons from OVX+E mice. Blocking action potentials eliminated the effect on frequency, indicating presynaptic actions. Amplitude changes were due to postsynaptic actions. Kisspeptin also increased frequency of glutamatergic excitatory PSCs in cells from OVX+E animals. Kisspeptin did not affect either GABAergic or glutamatergic transmission to GnRH neurons in cells from OVX mice, indicating effects on transmission are estradiol dependent. In contrast to stimulatory effects on GABAergic PSC frequency during negative feedback, kisspeptin had no effect during positive feedback. These data suggest estradiol enables kisspeptin-mediated increases in GABA and glutamate transmission to GnRH neurons. Furthermore, the occlusion of the response during positive feedback implies one consequence of estradiol positive feedback is an increase in transmission to GnRH neurons mediated by endogenous kisspeptin.

scholarly journals Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction

2018 ◽  
Author(s):  
Luhong Wang ◽  
Charlotte Vanacker ◽  
Laura L. Burger ◽  
Tammy Barnes ◽  
Yatrik M. Shah ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Knockout Mice ◽  
Positive Feedback ◽  
Gonadotropin Releasing Hormone ◽  
Genetic Dissection ◽  
Female Reproduction ◽  
Releasing Hormone ◽  
Gnrh Neurons ◽  
Reproductive Cycles ◽  
The Brain

AbstractThe brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Estradiol induces negative feedback on pulsatile GnRH/luteinizing hormone (LH) release and positive feedback generating preovulatory GnRH/LH surges. Negative and positive feedback are postulated to be mediated by kisspeptin neurons in arcuate and anteroventral periventricular (AVPV) nuclei, respectively. Kisspeptin-specific ERα knockout mice exhibit disrupted LH pulses and surges. This knockout approach is neither location-specific nor temporally-controlled. We utilized CRISPR-Cas9 to disrupt ERα in adulthood. Mice with ERα disruption in AVPV kisspeptin neurons have typical reproductive cycles but blunted LH surges, associated with decreased excitability of these neurons. Mice with ERα knocked down in arcuate kisspeptin neurons showed disrupted cyclicity, associated with increased glutamatergic transmission to these neurons. These observations suggest activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from its role in the development of hypothalamic kisspeptin neurons or puberty onset.Significant StatementThe brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Ovarian estradiol regulates GnRH pulses (negative feedback) and the GnRH surge release that ultimately triggers ovulation (positive feedback). Kisspeptin neurons in the arcuate and anteroventral periventricular nuclei are postulated to convey negative and positive feedback to GnRH neurons, respectively. Kisspeptin-specific ERα knockout mice exhibited disrupted negative and positive feedback. However, it is not clear what roles each kisspeptin population plays, and not possible to separate their roles during development vs adulthood in this model. Here we utilized CRISPR-Cas9 to disrupt ERα in each population in adulthood. We found activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from estradiol action during development.

scholarly journals Gonadotropin-Releasing Hormone (GnRH) Activates the M-Current in GnRH Neurons: An Autoregulatory Negative Feedback Mechanism?

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2459-2466 ◽  
Author(s):  
Chun Xu ◽  
Troy A. Roepke ◽  
Chunguang Zhang ◽  
Oline K. Rønnekleiv ◽  
Martin J. Kelly
Keyword(s):  
Negative Feedback ◽  
Feedback Mechanism ◽  
Gonadotropin Releasing Hormone ◽  
Releasing Hormone ◽  
M Current ◽  
Negative Feedback Mechanism ◽  
Gnrh Neurons

scholarly journals A CRH Receptor Type 1 Agonist Increases GABA Transmission to GnRH Neurons in a Circulating-Estradiol-Dependent Manner

Endocrinology ◽  
2020 ◽  
Vol 161 (11) ◽  
Author(s):  
Chayarndorn Phumsatitpong ◽  
Rose M De Guzman ◽  
Damian G Zuloaga ◽  
Suzanne M Moenter
Keyword(s):  
Brain Slices ◽  
Potassium Currents ◽  
Neuron Activity ◽  
Dependent Manner ◽  
Gnrh Neuron ◽  
Factors Affecting ◽  
Voltage Gated ◽  
Gnrh Neurons ◽  
As Stress ◽  
Gaba Transmission

Abstract GnRH neurons are central regulators of reproduction and respond to factors affecting fertility, such as stress. Corticotropin-releasing hormone (CRH) is released during stress response. In brain slices from unstressed controls, CRH has opposite, estradiol-dependent effects on GnRH neuron firing depending on the CRH receptor activated; activating CRHR-1 stimulates whereas activating CRHR-2 suppresses activity. We investigated possible direct and indirect mechanisms. Mice were ovariectomized and either not treated further (OVX) or given a capsule producing high positive feedback (OVX + E) or low negative feedback (OVX + low E) physiologic circulating estradiol levels. We tested possible direct effects on GnRH neurons by altering voltage-gated potassium currents. Two types of voltage-gated potassium currents (transient IA and sustained IK) were measured; neither CRHR-1 nor CRHR-2 agonists altered potassium current density in GnRH neurons from OVX + E mice. Further, neither CRH nor receptor-specific agonists altered action potential generation in response to current injection in GnRH neurons from OVX + E mice. To test the possible indirect actions, GABAergic postsynaptic currents were monitored. A CRHR-1 agonist increased GABAergic transmission frequency to GnRH neurons from OVX + E, but not OVX, mice, whereas a CRHR-2 agonist had no effect. Finally, we tested if CRH alters the firing rate of arcuate kisspeptin neurons, which provide an important excitatory neuromodulatory input to GnRH neurons. CRH did not acutely alter firing activity of these neurons from OVX, OVX + E or OVX + low E mice. These results suggest CRH increases GnRH neuron activity in an estradiol-dependent manner in part by activating GABAergic afferents. Mechanisms underlying inhibitory effects of CRH remain unknown.

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