Estradiol Induces Hypothalamic Dendritic Spines by Enhancing Glutamate Release: A Mechanism for Organizational Sex Differences
Open accessAbstract
The naturally occurring sex difference in dendritic spine number on hypothalamic neurons offers a unique opportunity to investigate mechanisms establishing synaptic patterning during perinatal sensitive periods. A major advantage of the rat as a model of sexual differentiation is that treatment of neonatal females with estradiol will permanently induce the male phenotype. During the development of other systems, exuberant innervation is followed by activity-dependent pruning necessary for elimination of spurious synapses. In contrast, we demonstrate that estradiol-induced organization in the hypothalamus involves the induction of new synapses on dendritic spines. Activation of estrogen receptors by estradiol triggers a nongenomic activation of PI3 kinase that results in enhanced glutamate release from presynaptic neurons. Subsequent activation of ionotropic glutamate receptors activates MAP kinases, thereby inducing dendritic spine formation. These results reveal a transneuronal mechanism by which estradiol acts during a sensitive period to establish a profound and lasting sex difference in hypothalamic synaptic patterning.
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The study of sex differences in the brain has revealed similarities and dissimilarities in neuronal development mechanisms between the sexes.
“The study of sex differences in the brain has unveiled similarities and dissimilarities in the mechanism of neuronal development between sexes (Amateau & McCarthy, 2004; McCarthy & Arnold, 2011; Schwarz, Liang, Thompson, & McCarthy, 2008).”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Schwarz, Liang, Thompson, & McCarthy, 2008
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Sexual Differentiation of Brain and Behavior
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Self-citationThe Year In Neuroendocrinology
Blaustein, J. D. (2009) · Molecular Endocrinology · doi:10.1210/me.2009-0350 · Cited by 19 · see citing works
A lumpers versus splitters approach to sexual differentiation of the brain
McCarthy, M. M. (2011) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2011.01.004 · Cited by 14 · see citing works
“A similar scenario is found in the immediately adjacent mediobasal hypothalamus where estradiol also induces the formation of dendritic spine synapses, also by co-opting glutamate, and the effects are also reproducible in the dish, meaning they are local to the hypothalamus [25].”
BackgroundSelf-citationAndrogen and estrogen actions on male physical activity: a story beyond muscle
Jardí, F., Laurent, M. R., Dubois, V., Kim, N., Khalil, R., Decallonne, B., Vanderschueren, D., & Claessens, F. (2018) · Journal of Endocrinology · doi:10.1530/joe-18-0125 · Cited by 20 · see citing works
The neuroendocrine control of sex specific behavior in vertebrates: lessons from mammals and birds.
McCarthy, M., & Ball, G. (2008) · Current Topics in Developmental Biology · doi:10.1016/s0070-2153(08)00407-9 · Cited by 14 · see citing works
Self-citationCorbett, C. M., Miller, E. N., Wannen, E. E., Rood, B. D., Chandler, D. J., & Loweth, J. A. (2023) · Neuroendocrinology · doi:10.1159/000531351 · Cited by 13 · see citing works
“…the fact that estradiol can increase the probability of presynaptic glutamate release in areas such as the hippocampus [35] and the hypothalamus [36], one intriguing possibility is that cocaine exposure is facilitating or enhancing estradiol-induced alterations in glutamatergic transmission in…”
BackgroundJeffery, G. S., Peng, K. C., & Wagner, E. J. (2011) · Pharmaceuticals · doi:10.3390/ph4040630 · Cited by 13 · see citing works
Effects of estrogen on synapsin I distribution in developing hypothalamic neurons.
Ohtani-Kaneko, R., Iwafuchi, M., Iwakura, T., Muraoka, D., Yokosuka, M., Shiga, T., & Watanabe, C. (2010) · Neurosciences research · doi:10.1016/j.neures.2009.10.012 · Cited by 13 · see citing works
Acosta-Martínez, M., Luo, J., Elias, C., Wolfe, A., & Levine, J. (2009) · Endocrinology · doi:10.1210/en.2008-1753 · Cited by 13 · see citing works
Nugent, B. M., Wright, C. L., Zup, S., & McCarthy, M. (2008) · Physiology and Behavior · doi:10.1016/j.physbeh.2008.10.007 · Cited by 13 · see citing works
Self-citationPhumsatitpong, C., Guzman, R. D. D., Zuloaga, D., & Moenter, S. (2020) · Endocrinology · doi:10.1210/endocr/bqaa140 · Cited by 12 · see citing works
Sakakibara, M., Deura, C., Minabe, S., Iwata, Y., Uenoyama, Y., Maeda, K., & Tsukamura, H. (2013) · Journal of neuroendocrinology · doi:10.1111/j.1365-2826.2012.02389.x · Cited by 11
Manyukhina, V. O., Orekhova, E. V., Prokofyev, A. O., Obukhova, T. S., & Stroganova, T. A. (2022) · PLoS ONE · doi:10.1371/journal.pone.0279868 · Cited by 10 · see citing works
“Estradiol also affects neuronal excitability via several pathways (Balthazart & Ball, 2006; Clemens et al., 2019; Huang et al., 2015; Kow et al., 2005; Schroeder et al., 2017; Schwarz et al., 2008; X. Wu et al., 2013; Y. W. C. Wu et al., 2014).”
BackgroundCellular localization of 5α-reductase in the rat cerebellum
Kiyokage, E., Toida, K., Suzuki-Yamamoto, T., & Ishimura, K. (2014) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2014.04.002 · Cited by 13 · see citing works
Schwarz, J. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802114-9.00010-x · Cited by 9 · see citing works
Self-citationGonadal hormone modulation of intracellular calcium as a mechanism of neuroprotection.
Zup, S., & Madden, A. M. K. (2016) · Frontiers in neuroendocrinology (Print) · doi:10.1016/j.yfrne.2016.02.003 · Cited by 8 · see citing works
“For example, estradiol induces spinogenesis in the developing medial basal hypothalamus (MBH) specifically by enhancing presynaptic glutamate release to increase NMDAR activation (Todd et al., 2005; Schwarz et al., 2008).”
McCarthy, M. M. (2010) · Colloquium Series on The Developing Brain · doi:10.4199/c00018ed1v01y201010dbr001 · Cited by 12 · see citing works
Self-citationRainville, J. R., Pollard, K., & Vasudevan, N. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00018 · Cited by 7 · see citing works
“Another model for the increase in 17β-E-mediated increase in spine density in the hypothalamus is that 17β-E stimulates PI3K activation pre-synaptically, inducing glutamate release, followed by NMDA receptor activation and ERK signaling post-synaptically, with a subsequent increase in spinophilin protein that was corr…”
Background
- Authors
- Schwarz, J. M., Liang, S.-L., Thompson, S. M., & McCarthy, M. M.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Schwarz, Jaclyn M.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 58
- Issue
- 4
- Pages
- 584-598
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2570057
- OpenAlex
- W2005704396
- Cited by
- 139
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 7 · 2022: 8 · 2021: 2 · 2020: 6 · 2019: 6 · 2018: 3 · 2017: 7 · 2016: 9 · 2015: 4 · 2014: 10 · 2013: 4 · 2012: 11
- FWCI
- 8.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1903 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Israel National Road Safety Authority (F31NSO55518, R01MH052716, R01MH065488)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- estradiol, dendritic spines, hypothalamus, sexual differentiation, glutamate release, PI3-kinase, ionotropic glutamate receptors, mitogen-activated protein kinase, presynaptic neurons, synaptic pruning
- MeSH terms
- Animals, Animals, Newborn, Drug Interactions, Estradiol, Female, Hypothalamus, Male, Neurons, Pregnancy, Quinoxalines, Sex Characteristics, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Dizocilpine Maleate, Silver Staining, Rats, Sprague-Dawley, Patch-Clamp Techniques, Excitatory Amino Acid Antagonists, Phosphatidylinositol 3-Kinases, Dendritic Spines, Rats, In Vitro Techniques
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