Elsevier

Brain Research

Volume 1364, 10 December 2010, Pages 35-43
Brain Research

Review
Glutamate regulation of GnRH neuron excitability

https://doi.org/10.1016/j.brainres.2010.08.071Get rights and content

Abstract

The gonadotropin-releasing hormone (GnRH) neuronal network is the master controller of the reproductive axis. It is widely accepted that the amino acid transmitters GABA and glutamate play important roles in controlling GnRH neuron excitability. However, remarkably few studies have examined the functional role of direct glutamate regulation of GnRH neurons. Dual-labeling investigations have shown that GnRH neurons express receptor subunits required for AMPA, NMDA and kainate signaling in a heterogeneous manner. Electrophysiological and calcium imaging studies have confirmed this heterogeneity and shown that while the majority of adult GnRH neurons express AMPA/kainate receptors, only small sub-populations have functional NMDA or metabotropic glutamate receptors. Accumulating evidence suggests that one important role of direct glutamate signaling at GnRH neurons is for their activation at the time of puberty. Whereas in vivo studies have indicated the importance of NMDA signaling within the whole of the GnRH neuronal network, including afferent neurons and glia, investigations at the level of the GnRH neuron suggest that peripubertal changes in AMPA receptor expression may be dominant in the mouse. The sources of glutamatergic inputs to the GnRH neurons are only just beginning to be examined and include the anteroventral periventricular nucleus as well as the possibility that GnRH neurons may use glutamate as a neurotransmitter in recurrent collateral innervation. It is expected that a full understanding of the glutamatergic regulation of GnRH neurons will provide significant insight into the mechanisms underlying their control of reproductive function.

Research Highlights

ā–ŗGnRH neurons possess AMPA, kainate, NMDA and metabotropic glutamate receptors. ā–ŗAt puberty there is an increased number of dendritic spines and AMPA receptors. ā–ŗGlutamatergic signaling displays plasticity across the estrus cycle. ā–ŗGlutamate signaling is important for regulating both puberty onset and pusatile LH secretion.

Section snippets

Morphological studies

There are three types of ionotropic glutamate receptors all of which appear to be expressed in GnRH neurons to different extents. Ī±-Amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors are glutamate receptors comprised of a combination of 4 subunits (GluR1-4 or GluR A-D). N-methyl-d-aspartic acid (NMDA) glutamate receptors are also comprised of four subunits (NR1-3); however, each functional receptor must possess at least one NR1 subunit. Finally, kainate-type glutamate receptors

Metabotropic glutamate receptors and GnRH neurons

Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors (GPCRs) that generally mediate slower neuromodulation (Bordi and Ugolini, 1999, Schoepp, 2001). There are 5 different mGluRs that are characterized as either Group I, II or III. Anatomical evidence indicates that group I mGluRs are primarily localized postsynaptically on neurons or on glial cells and signal through Gq/11 pathways. Activation of these receptors increases intracellular Ca2+ and IP3. Group II/III mGluRs are

Sources of glutamate inputs to GnRH neurons

To date, there is almost no information on the locations of the glutamatergic cell bodies giving rise to inputs to GnRH neurons. Although recent transgenic tracing studies have shown that GnRH neurons receive direct inputs from multiple brain regions (Campbell, 2007), which of these are glutamatergic is unknown. However, one highly likely site is the AVPV. This brain region is known to contain neurons that project to GnRH neurons in the rodent (Gu and Simerly, 1997, Simonian et al., 1999,

Are GnRH neurons themselves glutamatergic?

In 2004, Hrabovszky and colleagues reported that essentially all GnRH neurons expressed vGlut2 mRNA (Hrabovszky et al., 2004), a transporter necessary for accumulating glutamate into synaptic vesicles and considered a marker of a glutamatergic phenotype. Although previous and subsequent morphological studies had not found evidence for vGlut2 protein in GnRH neurons (Kiss et al., 2003, Sergeeva and Jansen, 2009), a recent investigation found that a vGlut2 promoter construct directed expression

Plasticity of glutamate transmission across puberty

Several studies suggest an important role of NMDA receptors, in particular, in the postnatal development and functioning of the hypothalamoā€“pituitaryā€“gonadal axis. Repetitive infusions of NMDA agonists can induce precocious puberty (Plant et al., 1989, Smyth and Wilkinson, 1994) whereas infusions of NMDA antagonists can delay puberty onset (Urbanski and Ojeda, 1990). In addition, NMDA antagonists can inhibit either spontaneous (Arslan et al., 1988, Brann and Mahesh, 1991) or stimulated LH

Plasticity of glutamate transmission across the estrous cycle

Changes in both the frequency of sEPSCs and the relative proportion of GnRH neurons showing both AMPA and NMDA sEPSCs have recently been reported over the course of the estrous cycle in the mouse (Christian et al., 2009). In particular, during the estrogen negative feedback stage of the cycle, there is reduced sEPSC frequency as well as reduced numbers of synapses showing only NMDA-mediated sEPSCs (Christian et al., 2009). One factor that controls GnRH neuron sEPSC frequency appears to be

Physiological impact of glutamate on GnRH neuron excitability and neuroendocrine function

While it is established that GnRH neurons express functional glutamate receptors, it is far less clear how important this glutamatergic signaling is in controlling the excitability of GnRH cells under physiological conditions. Many studies have shown that exogenous glutamate agonists or antagonists injected into the brain can stimulate or inhibit LH secretion respectively (Brann and Mahesh, 1991, Lopez et al., 1990, Ondo et al., 1976, Ping et al., 1997, Price et al., 1978, Urbanski and Ojeda,

Conclusions

Many data support the concept that glutamate signaling at GnRH neurons is important in controlling their excitability, and hence, GnRH secretion from the median eminence. In addition, the normal postnatal development of the GnRH system at puberty is also likely to be regulated by glutamatergic transmission (Fig.Ā 4). However, in comparison with the GABA, relatively little attention has been focused on glutamatergic regulation of GnRH neurons. In part, this may have resulted from the likely

Acknowledgments

Studies in the authors' laboratories reported here have been supported by the New Zealand Health Research Council and Royal Society Marsden Fund.

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