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Division of Pharmacology & Toxicology, College of Pharmacy and Institute for Neuroscience and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712
Address all correspondence and requests for reprints to: Dr. Andrea C. Gore, Division of Pharmacology/Toxicology A1915, The University of Texas at Austin, Austin, Texas 78712. E-mail: andrea.gore{at}mail.utexas.edu.
The seemingly endless variety of inputs to hypothalamic GnRH neurons has puzzled investigators for decades. To all appearances, GnRH cells are able to recognize and respond to virtually every neurotransmitter in the central nervous system. Although this complexity may seem redundant, this is probably not the case; each input likely represents a unique mechanism for conveying specific information about the external and internal environment to GnRH neurons. Despite the abundance of afferent inputs to GnRH cells, investigators typically consider GnRH neurons as having a single output: the GnRH peptide. This concept is challenged by the study of E. Hrabovszky et al. in the present issue of Endocrinology (1), who provide new evidence that GnRH neurons of the rat also have a glutamatergic phenotype.
Glutamate, the principal excitatory neurotransmitter in the hypothalamus (2), has been recognized for many years as being a major regulatory input to GnRH neurons. Although previously controversial, there is now strong evidence from rats and mice that GnRH cells express glutamate receptors [both NMDA (N-methyl-D-aspartate) and non-NMDA] at their perikarya and their nerve terminals (3, 4, 5, 6, 7, 8, 9, 10). GnRH cells also exhibit direct electrophysiological responses to glutamate application (11, 12, 13), suggesting that these glutamate receptors are functional. Although the source of glutamatergic input to GnRH neurons is not entirely clear, local glutamatergic circuits exist in the hypothalamus (14, 15), and glutamate release can be measured in the preoptic area and medial basal hypothalamus of rodents (16, 17, 18).
The study by E. Hrabovszky et al. (1) provides tantalizing data that GnRH neurons themselves synthesize, and potentially release, glutamate. Using male Wistar rats, they examined coexpression of GnRH with the vesicular glutamate transporter-2 (VGLUT2). To date three VGLUTs have been described, each with distinct localizations in the central nervous system (19). VGLUTs enable the accumulation of glutamate into synaptic vesicles, thereby conferring the ability for a cell to secrete glutamate; hence, the presence of a VGLUT in a cell implies a glutamatergic phenotype (20). Using dual in situ hybridization of GnRH mRNA together with VGLUT2 mRNA at the level of GnRH perikarya, Hrabovszky et al. demonstrated that virtually all GnRH somata (99.5%) of adult male rats coexpress VGLUT2 mRNA. They also showed that GnRH-immunoreactive terminals in circumventricular regions (the organum vasculosum of the lamina terminalis and the median eminence) coexpress VGLUT2 protein, using dual immunohistochemistry. Together, these results suggest that GnRH neurons are glutamatergic.
These exciting findings challenge three previous studies reporting that, although GnRH neurons are in close contact or apposition to glutamatergic neurons, they are not glutamatergic themselves. Using electron microscopy to investigate the relationship between GnRH nerve terminals and glutamate immunoreactive processes in the median eminence of ovariectomized female Wistar-Imamichi rats, Kawakami et al. (6) found appositions between 91% of GnRH neuroterminals with glutamate immunoreactive processes but no coexpression (6). Kiss et al. (21) showed, using electron microscopy of intact male and female Sprague Dawley rats, that VGLUT2-immunoreactive axon terminals contact GnRH neurons on the cell somata or proximal dendrite with asymmetric (excitatory) synapses. However, they did not report any double-labeling of VGLUT2 and GnRH immunoreactivity. Finally, a recent confocal microscopy study in intact female Sprague Dawley rats by Lin et al. (22) reported contacts between GnRH-immunoreactive perikarya and VGLUT2-immunoreactive boutons but no double labeling. In their paper, Hrabovszky et al. (1) speculated that differences between their results and previous findings may be attributable to the greater sensitivity of their in situ hybridization protocol, which used an amplification method for detection of the VGLUT2 mRNA (23). However, the studies also differed in the sex, gonadal status (intact vs. castrated) and other methodological issues. Clearly additional experimentation will help to resolve the discrepancies. In particular, a demonstration that vesicles containing glutamate are located within GnRH terminals would extend the authors’ results and place them into a physiological context: that is, GnRH neurons may also secrete glutamate from synaptic vesicles.
Because GnRH processes express glutamate receptors (6, 7, 8), the authors’ finding of VGLUT2 coexpression in GnRH neurons (1) raises the possibility that glutamate, released from a GnRH terminal, can act on the terminal from which it was released. Such an autocrine mechanism could confer further stimulation (if positive regulation) or a diminution (if negative regulation) of GnRH neurosecretion. In addition, local glutamate released from GnRH terminals may act locally on other non-GnRH neuroterminals in the median eminence, thereby exerting paracrine regulation of other hypothalamic releasing hormones. This would be a potential mechanism for cross talk among neuroendocrine systems.
The possibility that GnRH neurons may also release glutamate adds to the intricacy of the GnRH neuronal network. First, as mentioned earlier, GnRH neurons receive a wide variety of afferent inputs at their perikarya and neuroterminals. Second, GnRH neurons themselves can coexpress other neurotransmitters. Besides glutamate, subpopulations of GnRH neurons of rodents have been shown to coexpress the neuropeptides galanin (24), 
-sleep-inducing peptide (25), cholecystokinin (26), and neurotensin (26), and the neurotrophic factor, IGF-I (27, 28). However, to my knowledge, no laboratory has investigated whether GnRH neurons actually secrete any of these factors. The finding of Hrabovszky et al. (1) that VGLUT2 is coexpressed in all GnRH neurons indicates that glutamate is packaged into synaptic vesicles, and strongly supports the possibility that GnRH neuroterminals can release glutamate. It would be particularly interesting in future studies to determine whether glutamate or any of the other neurotransmitters coexpressed in GnRH neurons are released in a pulsatile manner, together with the GnRH peptide. Now, along with the numerous synaptic inputs to GnRH neurons, we must consider a greater complexity of outputs from these critical cells involved in the regulation of vertebrate reproduction.
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Received July 6, 2004.
Accepted for publication July 6, 2004.
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