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Microglial Phagocytosis of Newborn Cells Is Induced by Endocannabinoids and Sculpts Sex Differences in Juvenile Rat Social Play
Open accessAbstract
Brain sex differences are established developmentally and generate enduring changes in circuitry and behavior. Steroid-mediated masculinization of the rat amygdala during perinatal development produces higher levels of juvenile rough-and-tumble play by males. This sex difference in social play is highly conserved across mammals, yet the mechanisms by which it is established are unknown. Here, we report that androgen-induced increases in endocannabinoid tone promote microglia phagocytosis during a critical period of amygdala development. Phagocytic microglia engulf more viable newborn cells in males; in females, less phagocytosis allows more astrocytes to survive to the juvenile age. Blocking complement-dependent phagocytosis in males increases astrocyte survival and prevents masculinization of play. Moreover, increased astrocyte density in the juvenile amygdala reduces neuronal excitation during play. These findings highlight novel mechanisms of brain development whereby endocannabinoids induce microglia phagocytosis to regulate newborn astrocyte number and shape the sexual differentiation of social circuitry and behavior. VIDEO ABSTRACT.
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“Similarly, blocking testosterone by using an androgen receptor antagonist in females treated with testosterone completely prevents these effects (VanRyzin et al., 2019).”
From Developmental origins of sex differences in the neural circuitry of play (2020) · cites this paper as VanRyzin et al., 2019
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“Lower astrocyte density in the MeA is correlated for male-typical levels of play (VanRyzin et al., 2019).”
From Developmental origins of sex differences in the neural circuitry of play (2020) · cites this paper as VanRyzin et al., 2019
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“If females are treated with CB1 and CB2 receptor agonists to “mimic” the higher endocannabinoid levels, their newborn cell number and eventual play behavior is masculinized, even in the absence of testosterone (Argue et al., 2017; VanRyzin et al., 2019).”
From Developmental origins of sex differences in the neural circuitry of play (2020) · cites this paper as VanRyzin et al., 2019
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“Studies investigating the neural underpinnings of this behavioral sex difference have identified various nodes within the larger circuitry of social behavior, including the medial amygdala (VanRyzin et al., 2019) and lateral septum (Bredewold et al., 2014), which exert sex-specific influences on play following sexual differentiation early in life as part of typical brain development.”
From Social play experience in juvenile rats is indispensable for appropriate socio-sexual behavior in adulthood in males but not females (2023) · cites this paper as VanRyzin et al., 2019
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Cites
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Synaptic Pruning by Microglia Is Necessary for Normal Brain Development
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Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
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The Classical Complement Cascade Mediates CNS Synapse Elimination
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Microglia Shape Adult Hippocampal Neurogenesis through Apoptosis-Coupled Phagocytosis
Sierra, A., Encinas, J. M., Deudero, J. J. P., Chancey, J. H., Enikolopov, G., Overstreet-Wadiche, L. S., Tsirka, S. E., & Maletic-Savatic, M. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.08.014 · Cited by 1,622
Microglia Regulate the Number of Neural Precursor Cells in the Developing Cerebral Cortex
Cunningham, C. L., Martínez-Cerdeño, V., & Noctor, S. C. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.3441-12.2013 · Cited by 976
Microglial Phagocytosis of Live Neurons
Brown, G. C., & Neher, J. J. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3710 · Cited by 853
Layer V cortical neurons require microglial support for survival during postnatal development
Ueno, M., Fujita, Y., Tanaka, T., Nakamura, Y., Kikuta, J., Ishii, M., & Yamashita, T. (2013) · Nature Neuroscience · doi:10.1038/nn.3358 · Cited by 781
Microglia Promote the Death of Developing Purkinje Cells
Marı́n-Teva, J. L., Dusart, I., Colin, C., Gervais, A., van Rooijen, N., & Mallat, M. (2004) · Neuron · doi:10.1016/s0896-6273(04)00069-8 · Cited by 757
Reframing sexual differentiation of the brain
McCarthy, M. M., & Arnold, A. P. (2011) · Nature Neuroscience · doi:10.1038/nn.2834 · Cited by 728
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Microglia states and nomenclature: A field at its crossroads
Paolicelli, R. C., Sierra, A., Stevens, B., Tremblay, M.-E., Aguzzi, A., Ajami, B., Amit, I., Audinat, E., Bechmann, I., Bennett, M., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.020 · Cited by 1,973
The Semantics of Microglia Activation: Neuroinflammation, Homeostasis, and Stress
Woodburn, S. C., Bollinger, J. L., & Wohleb, E. S. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02309-6 · Cited by 783
Microglia morphophysiological diversity and its implications for the CNS
Vidal-Itriago, A., Radford, R. A. W., Aramideh, J. A., Maurel, C., Scherer, N. M., Don, E. K., Lee, A., Chung, R. S., Graeber, M. B., & Morsch, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.997786 · Cited by 451
Microglia Actively remodel adult hippocampal neurogenesis through the phagocytosis secretome
Diaz-Aparicio, I., Paris, I., Sierra-Torre, V., Plaza-Zabala, A., Rodríguez-Iglesias, N., Márquez-Ropero, M., Beccari, S., Huguet, P., Abiega, O., Alberdi, E., et al. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.0993-19.2019 · Cited by 333
Shaping Neuronal Fate: Functional Heterogeneity of Direct Microglia-Neuron Interactions
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Metadata
- Authors
- VanRyzin, J. W., Marquardt, A. E., Argue, K. J., Vecchiarelli, H. A., Ashton, S. E., Arambula, S. E., Hill, M. N., & McCarthy, M. M.
- Affiliations
- University of Maryland, Baltimore (US)
- University of Calgary (CA)
- Corresponding author
- McCarthy, Margaret M.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 102
- Issue
- 2
- Pages
- 435-449.e6
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC8046232
- OpenAlex
- W2918315099
- Cited by
- 272
- References
- 65
- Citations by year
- 2026: 20 · 2025: 31 · 2024: 48 · 2023: 44 · 2022: 41 · 2021: 36 · 2020: 38 · 2019: 14
- FWCI
- 19.53
- Type
- journal article
- Language
- en
- Update notices
- erratum (2022-04-06)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01MH52716, R01DA039062)
- Natural Sciences and Engineering Council of Canada
- Canadian Institutes of Health Research
- CIHR
- Alberta Innovates
- BranchOut Neurological Foundation
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Keywords
- microglial phagocytosis, endocannabinoids, sex differences, social play, rough-and-tumble play, amygdala development, masculinization, androgens, astrocyte survival, neuronal excitation, social behavior, sexual differentiation of the brain
- MeSH terms
- Amygdala, Androgen Antagonists, Androgens, Animals, Animals, Newborn, Arachidonic Acids, Astrocytes, Behavior, Animal, Cell Survival, Complement System Proteins, Female, Flutamide, Glycerides, Male, Phagocytosis, Play and Playthings, Sex Characteristics, Social Behavior, Testosterone, Microglia, Rats, Polyunsaturated Alkamides, Endocannabinoids
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