Synaptic integration in hypothalamic gonadotropin releasing hormone (GnRH) neurons

Abstract

The impact of the A-type γ-aminobutyric acid (GABA-A) receptor in gonadotropin releasing hormone (GnRH) neurons is controversial. In adult GnRH neurons, the GABA-A receptor conductance has been reported to either hyperpolarize or depolarize GnRH neurons. Regardless of whether GABA is inhibitory or excitatory in GnRH neurons, GABAergic input would be integrated with post-synaptic potentials generated by other synaptic inputs. We used dynamic current clamping and compartmental computer modeling to examine the integration of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamatergic input and GABA-mediated input in both the hyperpolarizing (inhibitory) and depolarizing (excitatory) modes. In both living and model neurons, action potentials were most likely a few ms after a maximum in AMPA conductance coincided with a minimum in inhibitory GABA. Excitatory GABA interacted differently with AMPA, with spikes most likely, in both dynamic clamping of living neurons and in model neurons, when a maximum in AMPA coincided with the decay from peak of a maximum in GABA. Distributing synapses along the dendrite maximized the temporal relationship between AMPA and GABA conductances and therefore, the potential for spiking. Thus, these two dominant neurotransmitters could interact in multiple frames to generate action potentials in GnRH neurons. KeywordsGnRH; synaptic integration; compartmental model; glutamate; GABA; hypothalamus Hypothalamic GnRH neurons form the final pathway for integration of signals regulating reproduction. The control of GnRH neurons has been proposed to reflect both their intrinsic electrical properties and the input they receive from presynaptic neurons (Kusano et al., 1995; reviewed by Lopez et al., 1998). Despite the relatively precise requirements in the timing of GnRH pulses for proper reproductive function (Pohl et al., 1983), GnRH neurons have heterogeneous electrophysiological properties (Sim et al., 2001;Spergel et al., 1999). Moreover, emerging evidence suggests that GnRH neurons may differ in their responses to at Corresponding author: Kelly Suter, University of Texas at San Antonio, 1 UTSA Circle, San Antonio TX, 78249. kelly.suter@utsa.edu. Requested Section Editor: Menahem Segal, Department of Neurobiology, Weizmann Institute of Science (Rehovot, Israel) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2009 July 17. Published in final edited form as:Neuroscience. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manus...

Estradiol Suppresses Glutamatergic Transmission to Gonadotropin-Releasing Hormone Neurons in a Model of Negative Feedback in Mice1

“…Another possibility is that one subpopulation of GnRH neurons may receive elevated GABA transmission but no glutamate transmission during positive feedback, while another subpopulation is targeted for increases in both GABA and glutamate transmission. Recent modeling work suggests that synaptic GABA and AMPA inputs can interact to modulate, and in some cases amplify, action potential firing in GnRH neurons [59]. In this regard, blocking of ionotropic GABA and glutamate receptors in brain slices disrupts the normal pattern of GnRH neuron firing during both negative feedback and positive feedback [41].…”

A simple integrative electrophysiological model of bursting GnRH neurons

“…Considering earlier results that underline the importance of dendritic mechanisms in the case of GnRH neurons (Campbell et al, 2009;Roberts et al, 2006;Roberts, Hemond, & Suter, 2008) which may contribute to the description of AP generation (Roberts, Campbell, et al, 2008), bursting (Izhikevich, 2005) and DAPs (Roberts et al, 2009), we take into account an active dendritic compartment. Furthermore, because the majority of our measurement data originates from bipolar GnRH neurons, a second, passive dendritic compartment is also incorporated in the model.…”

“…This aim was fulfilled with the application of a simplified model for the description of AP generation, which reduced the model complexity compared to previous results Duan et al, 2011) regarding the models of GnRH neuronal bursting. In addition, the proposed model is capable of the description of depolarizing afterpotentials, simple somato-dendritic interactions (see (Roberts et al, 2006;Roberts, Hemond, & Suter, 2008;Roberts et al, 2009)), and approximated reproduction of the shape of single APs. Furthermore, during model development, the parameters of the voltage dependent calcium current were determined according to (Kato et al, 2003).…”

“…A couple of models have been constructed so far to describe the ionic currents and short term (considering scales of milliseconds) general electrophysiological (Csercsik et al, 2010), and dendritic properties (Roberts et al, 2006;Roberts, Hemond, & Suter, 2008;Roberts et al, 2009) of GnRH neurons based on measurements performed on cells from hypothalamic slices. Other mathematical models (LeBeau *Manuscript Click here to download Manuscript: GnRH_neuron_RR_2_bbl.tex Click here to view linked References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 et Van Goor et al, 2000;Fletcher & Li, 2009) have been proposed to explain experimental data obtained on GT1 cells.…”

“…In addition the authors form a mathematical model to demonstrate that Ca 2+ dependent potassium currents may control the bursting behavior. The aims of our present work are to simplify this model and also to simultaneously incorporate one active and one passive dendritic compartment (to make it able to describe dendritic AP generation (Roberts, Hemond, & Suter, 2008) in bipolar GnRH neurons), and a current corresponding to a possible mechanism which has not been taken into account in the original model . This mechanism is the assumed Ca 2+ dependent regulation of sodium channels which, as we will show later, makes the model able to explain depolarizing afterpotentials (DAPs or afterdepolarizations ADPs).…”