A critical period in Purkinje cell development is mediated by local estradiol synthesis, disrupted by inflammation and has enduring consequences only for males
Open accessAbstract
UNLABELLED: Identifying and understanding critical periods in brain development is essential to decoding the long-term impact of widespread, poorly defined, and frequently occurring insults such as inflammation. Using the laboratory rat Rattus norvegicus, we have discovered a narrowly constrained critical period in Purkinje neuron development subject to dysregulation by inflammation. The onset and offset of heightened vulnerability are attributed to a tightly orchestrated gene expression profile present only during the second postnatal week and not the first or third weeks. Genes expressed during this time code for enzymes and receptors which are critical not only for prostaglandin production and activity but also for estradiol production via the aromatase enzyme and estradiol action via the α isoform of the estrogen receptor. The two synthetic pathways are connected by prostaglandin E2 (PGE2) activation of the aromatase enzyme, as we reported previously (Dean et al., 2012b) and confirm here. Dysregulation of the PGE2-estradiol pathway during the second week by treatment with PGE2 or lipopolysaccharides produces enduring consequences as a result of reduced growth of Purkinje dendritic trees and impaired juvenile social play behavior, but only in males. The deleterious consequences of inflammation locally in the cerebellum are prevented by peripheral treatment with the cyclooxygenase inhibitor nimesulide or the aromatase inhibitor formestane. These findings highlight a novel regulatory pathway that creates a critical period in brain development vulnerable to dysregulation by inflammation. SIGNIFICANCE STATEMENT: The cerebellum is increasingly appreciated for its role in social, emotional, and cognitive behaviors. It is consistently and severely affected in neuropsychiatric disorders originating during development, such as autism spectrum disorder and schizophrenia. We have identified a critical period in rat development during the second week of life that is dysregulated by inflammatory insults. An intrinsic program of gene expression determines the critical period. The enduring consequences of inflammation during the second postnatal week are stunted dendrites of the cerebellum's principal neurons, Purkinje cells, and impairments in later social behavior. These changes are not evident if inflammation occurs during the first or third week, highlighting the importance of fine-grained analyses of developmental processes and the factors that influence them.
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Kayedi-Bakhtiari, N., & Vatanparast, J. (2025) · Behavioural Brain Research · doi:10.1016/j.bbr.2025.115714 · Cited by 2 · see citing works
Moussa‐Tooks, A. B., Hetrick, W. P., & Green, J. T. (2020) · Neurobiology of Stress · doi:10.1016/j.ynstr.2020.100242 · Cited by 2 · see citing works
Seiffe, A., Kazlauskas, N., Campolongo, M., & Depino, A. M. (2024) · Scientific Reports · doi:10.1038/s41598-024-62217-6 · Cited by 2 · see citing works
Sex and the Developing Brain Second Edition
McCarthy, M. M. (2017) · Colloquium Series on The Developing Brain · doi:10.4199/c00152ed1v01y201703dbr014 · Cited by 2 · see citing works
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Orphan G Protein‐Coupled Receptors: A Novel Research Frontier in Autism and Associated Disorders
Gholamalizadeh, H., Rahimi, V. B., & Askari, V. R. (2025) · Archiv der Pharmazie · doi:10.1002/ardp.70018 · Cited by 1 · see citing works
Kissoondoyal, A., Ho, K., Wong, C. T., & Crawford, D. A. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.12.562077 · Cited by 1 · see citing works
Considerations on the Use of Aromatase Inhibitors in Postmenopausal Women With Breast Cancer
Blaustein, J. D. (2020) · Oxford University Press eBooks · doi:10.1093/oso/9780190645908.003.0023
Early-childhood inflammation blunts the transcriptional maturation of cerebellar neuronsPreprint
Ament, S. A., Cortes-Gutierrez, M., Herb, B. R., Mocci, E., Colantuoni, C., & McCarthy, M. M. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.07.26.501598
Postnatal Development of Neuroimmune Responses
Spencer, S. J. (2023) · Masterclass in neuroendocrinology · doi:10.1007/978-3-031-21358-8_9
Interplay of Sex, Gender, and Environment in Psychiatric Disorders
Agarwal, V. (2025) · Indian Journal of Social Psychiatry · doi:10.4103/ijsp.ijsp_139_25
Sex-specific alterations of niacin flush pathway biomarkers in schizophrenia
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- Authors
- Hoffman, J. F., Wright, C. L., & McCarthy, M. M.
- Affiliations
- University of Maryland, Baltimore (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-09-28
- Volume
- 36
- Issue
- 39
- Pages
- 10039-10049
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5039254
- OpenAlex
- W2525963595
- Cited by
- 57
- References
- 55
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 9 · 2018: 6 · 2017: 7 · 2016: 1
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (F31MH096532, R01MH091424)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- critical period, cerebellum, inflammation, estradiol synthesis, aromatase, prostaglandin E2, estrogen receptor alpha, lipopolysaccharide, dendritic development, social play, sex differences, nimesulide, formestane, cyclooxygenase inhibition, autism spectrum disorder, schizophrenia
- MeSH terms
- Aging, Animals, Critical Period, Psychological, Dendrites, Estradiol, Inflammation, Male, Purkinje Cells, Rats, Sprague-Dawley, Gene Expression Regulation, Developmental, Cell Enlargement, Rats, Neurogenesis
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