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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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“Although GABA is most commonly considered to be an inhibitory neurotransmitter in the central nervous system, most mature GnRH neurons showed an unusual characteristic, in that they are excited by GABA activation (DeFazio et al., 2002; Watanabe et al., 2014).”
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BackgroundPhysiology of Gnrh and Gonadotropin Secretion
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“The role of GABA on GnRH neuronal activity is debated since inhibitory and stimulatory effects have been observed depending on the protocols used, the presence of sex steroid treatment, the timing in the estrus cycle and the hypothalamic region studied (44, 45).”
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“Whether GABA is inhibitory or excitatory to GnRH neurons had been contentious, but the predominant action of GABA on GnRH neurons appears to be excitation.(109,110) It is reported that GABA is co-expressed in 20–75% of AVPV kisspeptin neurons,(111,112) implying that GABA along with kisspeptin released from the kisspep…”
BackgroundGABAergic Neurons and Their Modulatory Effects on GnRH3 in Zebrafish
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“and involve activation of these neurons at puberty in mammals [104], and similar processes could be at work”
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“Our results showed that the levels of Abat mRNA, Rfrp-3 and Gabbr1 decreased, but the expression of Kiss1 and Gnrh mRNA significantly increased after the addition of GABA-T inhibitors to hypothalamic neurons, consistent with the enhancement of GnRH neuronal activity and promotion of GnRH by GABA at the cellular level…”
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“Although 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 (Watanabe et al., 2014).”
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de Ávila, C., Chometton, S., Calvez, J., Guèvremont, G., Kania, A., Torz, L., Lenglos, C., Błasiak, A., ROSENKILDE, M. M., Holst, B., et al. (2020) · Neuroendocrinology · doi:10.1159/000513830 · Cited by 12
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“Gad2 encodes GAD65, which is preferred in presynaptic terminals for the synthesis of GABA for vesicle release [26].”
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“GABA is an inhibitory neurotransmitter, which has long been implicated as one of the major players in modulating GnRH neurons and LH secretion (Watanabe et al., 2014; Silva et al., 2019), the content of GABA in SD_28d was significantly increased over that in LD_28d.”
BackgroundKeogh, K. A., & Kenny, D. A. (2022) · animal · doi:10.1016/j.animal.2022.100527 · Cited by 11
Liu, Q., Liu, J. H., Wang, P., Zhang, Y., Li, B., Yu, Y., Dang, H., Li, H., Zhang, X., & Wang, Z. (2017) · Brain Research · doi:10.1016/j.brainres.2017.04.008 · Cited by 11
Baratange, C., Baali, H., Gaillet, V., Bonnard, I., Delahaut, L., Gaillard, J., Grandjean, D., Sayen, S., Gallorini, A., Bris, N. L., et al. (2023) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2023.165379 · Cited by 10
Pre‐ and post‐synaptic modulation by GABA B receptors of rat neuroendocrine dopamine neurones
Ammari, R., & Broberger, C. (2020) · Journal of Neuroendocrinology · doi:10.1111/jne.12881 · Cited by 10
Disorders of puberty and neurodevelopment: A shared etiology?
Read, J. E., Vasile‐Tudorache, A., Newsome, A., Lorente, M. J., Agustín‐Pavón, C., & Howard, S. R. (2024) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.15246 · Cited by 11
The impact of GABA and GABAergic pathway in polycystic ovary syndrome: a systematic review
Motafeghi, F. S., Amiri, M., Noroozzadeh, M., & Tehrani, F. R. (2025) · Obstetrics & Gynecology Science · doi:10.5468/ogs.24255 · Cited by 11
“This dysregulation of the GABAergic system is believed to contribute to increased GnRH and LH secretion as well as hyperandrogenism, as observed in animal models of PAE [21,45].”
Endocannabinoid System in the Neuroendocrine Response to Lipopolysaccharide-induced Immune Challenge
Laurentiis, A. D., Correa, F., & Fernández‐Solari, J. (2022) · Journal of the Endocrine Society · doi:10.1210/jendso/bvac120 · Cited by 10
Satake, H., & Sasakura, Y. (2023) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2023.112122 · Cited by 9
“In such cases, GABA primarily employs its ionotropic receptor; the intracellular concentration of chloride ions is elevated in the GnRH neurons, and binding of GABA to the receptor induces excitations through the efflux of this anion from the neurons (Ben-Ari, 2002; Watanabe et al., 2014).”
Bar-Sadeh, B., Amichai, O. E., Pnueli, L., Begum, K., Leeman, G., Emes, R. D., Stöger, R. J., Bentley, G. R., & Melamed, P. (2022) · BMC Biology · doi:10.1186/s12915-021-01219-6 · Cited by 9
“augment GnRH release at puberty through activating the stimulatory GABAA receptor [53, 54, 61].”
BackgroundSupasitdikul, T., Mazariegos, J. R. R., Nhat, N. N., Tung, Y., Yang, D., Lee, L., Gunawan, S. P., & Chen, Y. (2025) · Journal of Sleep Research · doi:10.1111/jsr.70125 · Cited by 7
Joshi, R., Yadav, P., Bagwe‐Parab, S., Tuli, H. S., Buttar, H. S., & Kaur, G. (2023) · Current Bioactive Compounds · doi:10.2174/1573407219666230210101925 · Cited by 6
Kusuma, P. S. W., & Hariani, D. (2017) · The Egyptian Journal of Aquatic Research · doi:10.1016/j.ejar.2017.10.006 · Cited by 7
Medrano, G. A., Singh, M., Plautz, E. J., Good, L. B., Chapman, K. M., Chaudhary, J., Jaichander, P., Powell, H. M., Pudasaini, A., Shelton, J. M., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/405985 · Cited by 7
“Disturbed GABAergic synaptic transmission in Pclo mutants likely affects the balance between inhibition and excitation and thereby provokes seizures, manifesting itself as epileptiform activity (Herbison and Moenter, 2011; Watanabe et al., 2014).”
BackgroundRodriguez-Sánchez, A. J., Meza-Herrera, C., Santiago-Miramontes, Á. D., Navarrete-Molina, C., Véliz-Deras, F., Ordoñez-Morales, J., Flores-Salas, J. M., & Marín-Tinoco, R. I. (2024) · Biology · doi:10.3390/biology13090656 · Cited by 7
“Another plausible WS-mechanism of the action could be its role as a facilitator, either in vitro and in vivo, based on the expression and release of GnRH throughout GABAergic neurons [50].”
BackgroundCiechanowska, M. O., Łapot, M., Kowalczyk, M., Malewski, T., Brytan, M., Antkowiak, B., & Przekop, F. (2019) · Pharmacological Reports · doi:10.1016/j.pharep.2019.02.019 · Cited by 6
Tong, H., Su, B., Liu, Z., & Chen, Y. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1054048 · Cited by 6
“In turn, NMDA can promote FSH secretion and GABA can regulate GnRH secretion (27, 28).”
BackgroundWu, N., Ning, K., Liu, Y., Wang, Q., Li, N., & Zhang, L. (2025) · Frontiers in Microbiology · doi:10.3389/fmicb.2025.1564902 · Cited by 7
“GABA acts as a critical inhibitory modulator of hypothalamic GnRH neurons by engaging GABA receptors, thereby suppressing GnRH secretion (Watanabe et al., 2014).”
Genomic Scanning of Inbreeding Depression for Litter Size in Two Varieties of Iberian Pigs
Hervás‐Rivero, C., Srihi, H., López‐Carbonell, D., Casellas, J., Ibáñez‐Escriche, N., Negro, S., & Varona, L. (2023) · Genes · doi:10.3390/genes14101941 · Cited by 5
“This inhibition is essential for the production of the GnRH hormone, which, in turn, is crucial for the synthesis of LH ( luteinizing hormone ) and FSH ( follicle-stimulating hormone ), both of which are crucial for reproduction [41–43].”
BackgroundAnatomy and Physiology of the Female Reproductive System
Vogazianou, A. (2019) · Springer eBooks · doi:10.1007/978-3-319-99817-6_38 · Cited by 5
Peng, J., Cui, Y., Liang, H., Xu, S. C., Weng, L., Meng, R., Ali, R., Wei, Q., Ruan, J., & Huang, J. (2024) · Animal nutrition · doi:10.1016/j.aninu.2024.08.009 · Cited by 4
Physiopathology, Diagnosis, and Treatment of Secondary Female Hypogonadism
Antoniou-Tsigkos, A., Μacut, D., & Mastorakos, G. P. (2018) · Endocrinology · doi:10.1007/978-3-319-44444-4_9 · Cited by 5
Yadav, A., & Mishra, R. K. (2025) · Journal of Reproductive Healthcare and Medicine · doi:10.25259/jrhm_27_2024 · Cited by 3
Abedi, H., Zarrin-Mehr, A., Ebrahimi, B., Haghshenas, H., Parvin, N., & Jahromi, H. K. (2024) · International Journal of Reproductive BioMedicine (IJRM) · doi:10.18502/ijrm.v22i3.16164 · Cited by 3
“In other words, if gamma-aminobutyric acid neurons are inhibited, an LH surge can be expected (25, 26).”
BackgroundPolymorphism and expression of GLUD1 in relation to reproductive performance in Jining Grey goats
Wang, W., Wang, Y., Liu, Y., Cao, G., Di, R., Wang, J., & Chu, M. (2023) · Archives animal breeding/Archiv für Tierzucht · doi:10.5194/aab-66-411-2023 · Cited by 3
Grid1 regulates the onset of puberty in female rats
Ye, J., Xiaoqian, L. I., Pan, Z., Zhuoya, W. U., Zhu, Y., Zhang, W., Lu, J., Shuangshuang, X. U., Qin, P., Ya, L. I. U., et al. (2024) · Journal of Veterinary Medical Science · doi:10.1292/jvms.23-0208 · Cited by 3
“The secretion of GnRH by neurons is affected by several factors, for example, γ-aminobutyric acid (GABA) has an inhibiting effect on GnRH secretion [ 33], and glutamate (Glu) promotes the secretion [11].”
Osmotic perception of GABAergic synaptic transmission in the supraoptic nucleus of rats
Ohbuchi, T., Saito, T., Yokoyama, T., Hashimoto, H., Maruyama, T., Suzuki, H., & Ueta, Y. (2020) · IBRO Reports · doi:10.1016/j.ibror.2020.06.007 · Cited by 3
“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 (Watanabe et al., 2014).”
BackgroundDemori, I., Siriya, S., & Burlando, B. (2025) · Applied Sciences · doi:10.3390/app151910483 · Cited by 2
Mohammadpour-Asl, S., Parvin, A., Akbari‐Gharalari, N., Asadi, N., Pooryai, A., & Roshan‐Milani, S. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.123778 · Cited by 2
Reversible Sterilization of Channel Catfish via Overexpression of Glutamic Acid Decarboxylase Gene
Ye, Z., Elaswad, A., Su, B., Alsaqufi, A. S., Shang, M., Bugg, W. S., Qin, G. T., Drescher, D., Li, H., Qin, Z., et al. (2024) · Animals · doi:10.3390/ani14131899 · Cited by 2
Multimodal GABAA receptor functions in the development of the central nervous system
Kumada, T., & Fukuda, A. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-823672-7.00014-4 · Cited by 2
Self-citationInfluence of Stress on the GnRH Neuronal Network
Grachev, P., & O'Byrne, K. T. (2018) · Wiley eBooks · doi:10.1002/9781119233275.ch14 · Cited by 2
Vagal nerve stimulation for the treatment of male factor infertility
Derakhshan, N., Yaghmaei, S., & Keshavarz, P. (2021) · Andrologia · doi:10.1111/and.14043 · Cited by 2
“Moreover, GABA plays a critical role in mediating both negative and positive estradiol feedback and controls the switch timing in estradiol feedback action (Watanabe et al., 2014).”
Background
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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