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The role of GABA in the regulation of GnRH neurons
Open accessAbstract
Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for the central regulation of reproduction. Gamma-amino butyric acid (GABA) has long been implicated as one of the major players in the regulation of GnRH neurons. Although GABA is typically an inhibitory neurotransmitter in the mature adult central nervous system, most mature GnRH neurons show the unusual characteristic of being excited by GABA. While many reports have provided much insight into the contribution of GABA to the activity of GnRH neurons, the precise physiological role of the excitatory action of GABA on GnRH neurons remains elusive. This brief review presents the current knowledge of the role of GABA signaling in GnRH neuronal activity. We also discuss the modulation of GABA signaling by neurotransmitters and neuromodulators and the functional consequence of GABAergic inputs to GnRH neurons in both the physiology and pathology of reproduction.
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![Figure 1 Excitatory action of GABA on rat GnRH neurons. (A) Representative [Ca2+]i response to 100 μM GABA. Most GnRH neurons showed [Ca2+]i increase in response to GABA. Some GnRH neurons did not respond to GABA. Some GnRH neurons showed [Ca2+]i decrease in response to GABA. (B) Muscimol (100 μM), a GABAA receptor agonist, increased [Ca2+]i in GnRH neurons. (C) Bicuculline (100 μM), a GABAA receptor antagonist, inhibited the [Ca2+]i increase induced by GABA. (D) GABA-induced [Ca2+]i increase was inhibited in Ca2+-free solution. (E) Bumetanide (100 μM), a blocker of NKCC1, reduced the GABA-induced [Ca2+]i increase. Muscimol and GABA were applied as indicated with horizontal bars. Bicuculline, Ca2+-free solution, and bumetanide were applied as indicated with open bars (Originally published in Watanabe et al., 2009a).](/paper-figures/b6dc525df0714f33b51414cfbc631b19/the-role-of-gaba-in-the-regulation-of-gnrh-neurons-figure-1.jpg)
![Figure 2 The intracellular Cl− concentration determines the polarity of GABA response. The GABA action is excitatory in immature neurons because [Cl−]i is high, owing to high levels of the Na+-K+-2Cl− cotransporter (NKCC1), which mediates inward transport of Cl−, and to low levels of the K+-Cl− cotransporter (KCC2), which excludes Cl− from the cell. In most neurons, the GABA response switches from excitation to inhibition during early postnatal development, due to the developmental decrease of the NKCC1 and increase of the KCC2. However, even in the mature neurons, neuronal damage down regulates the KCC2 and elevated Cl− concentration shifts GABA response from hyperpolarization to depolarization, occasionally excitation. Most GnRH neurons show the unusual characteristic of being excited by GABA in the adult brain.](/paper-figures/c9087b02279c499c8292653fc7d55f9d/the-role-of-gaba-in-the-regulation-of-gnrh-neurons-figure-2.jpg)
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“The activity of GnRH is regulated by neurotransmitters, steroid hormones, and growth factors (Watanabe, Fukuda, & Nabekura, 2014).”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Watanabe, Fukuda, & Nabekura, 2014
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“Different data converge to indicate that the LH surge is stimulated by glutamate [102,103] and inhibited by GABA [104,105]”
From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [104]
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Cites
Shrestha, S., & Offer, S. M. (2016) · Medical Epigenetics · doi:10.1159/000444713 · Cited by 8,951
Excitatory actions of gaba during development: the nature of the nurture
Ben-Ari, Y. (2002) · Nature Reviews Neuroscience · doi:10.1038/nrn920 · Cited by 2,448
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A role for kisspeptins in the regulation of gonadotropin secretion in the mouse
Gottsch, M. L., Cunningham, M. J., Smith, J. T., Popa, S. M., Acohido, B. V., Crowley, W. F., Seminara, S., Clifton, D. K., & Steiner, R. A. (2004) · Endocrinology · doi:10.1210/en.2004-0431 · Cited by 1,161
Han, S.-K., Gottsch, M. L., Lee, K. J., Popa, S. M., Smith, J. T., Jakawich, S. K., Clifton, D. K., Steiner, R. A., & Herbison, A. E. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.3328-05.2005 · Cited by 1,036
Immortalization of hypothalamic GnRH by genetically targeted tumorigenesis
Mellon, P. L., Windle, J. J., Goldsmith, P. C., Padula, C. A., Roberts, J. L., & Weiner, R. I. (1990) · Neuron · doi:10.1016/0896-6273(90)90028-e · Cited by 960
Cation-Chloride Cotransporters and Neuronal Function
Blaesse, P., Airaksinen, M. S., Rivera, C., & Kaila, K. (2009) · Neuron · doi:10.1016/j.neuron.2009.03.003 · Cited by 860
Two isoforms of glutamate decarboxylase: why?
Soghomonian, J., & Martin, D. L. (1998) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(98)01270-x · Cited by 643
Mechanism of Activity-Dependent Downregulation of the Neuron-Specific K-Cl Cotransporter KCC2
Rivera, C., Voipio, J., Thomas-Crusells, J., Li, H., Emri, Z., Sipilä, S., Payne, J. A., Minichiello, L., Saarma, M., & Kaila, K. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.5265-03.2004 · Cited by 515
Roles of the cation–chloride cotransporters in neurological disease
Kahle, K. T., Staley, K. J., Nahed, B. V., Gamba, G., Hébert, S., Lifton, R. P., & Mount, D. B. (2008) · Nature Clinical Practice Neurology · doi:10.1038/ncpneuro0883 · Cited by 430
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Oyola, M. G., & Handa, R. J. (2017) · Stress · doi:10.1080/10253890.2017.1369523 · Cited by 710
Salliss, M. E., Farland, L. V., Mahnert, N. D., & Herbst‐Kralovetz, M. M. (2021) · Human Reproduction Update · doi:10.1093/humupd/dmab035 · Cited by 298
Development and regulation of chloride homeostasis in the central nervous system
Watanabe, M., & Fukuda, A. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00371 · Cited by 244
“This discrepancy may be explained by low KCC2 protein levels and/or cell-type-specific (Watanabe et al., 2014) and/or sex-specific differences in the expression of KCC2 and NKCC1 (more KCC2 and less NKCC1 in females; Perrot-Sinal et al., 2007).”
BackgroundSelf-citationγ-Aminobutyric Acid (GABA): Biosynthesis, Role, Commercial Production, and Applications
Rashmi, D., Zanan, R. L., John, S., Khandagale, K. S., & Nadaf, A. B. (2018) · Studies in natural products chemistry · doi:10.1016/b978-0-444-64057-4.00013-2 · Cited by 175
Hypothalamo-Pituitary axis and puberty
Spaziani, M., Tarantino, C., Tahani, N., Gianfrilli, D., Sbardella, E., Lenzi, A., & Radicioni, A. F. (2020) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2020.111094 · Cited by 176
Metadata
- Authors
- Watanabe, M., Fukuda, A., & Nabekura, J.
- Affiliations
- Hamamatsu University (JP)
- The Graduate University for Advanced Studies, SOKENDAI (JP)
- Corresponding author
- Watanabe, Miho
- Venue
- Frontiers in Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2014-11-28
- Volume
- 8
- Pages
- 387-387
- ISSN
- 1662-453X (ISSN-L)
- PMC
- PMC4246667
- OpenAlex
- W2135581544
- Cited by
- 140
- References
- 111
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 12 · 2023: 12 · 2022: 12 · 2021: 12 · 2020: 17 · 2019: 13 · 2018: 9 · 2017: 12 · 2016: 10 · 2015: 9
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Japan Society for the Promotion of Science (26670512, 25460312, 25293052)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Reproductive Medicine › Reproductive Biology and Fertility
- Keywords
- GABA, GnRH neurons, GABAergic inhibition, neuroendocrine regulation of reproduction, neurotransmitter modulation, neuromodulators, GABA receptors, reproductive physiology, reproductive disorders
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