The DOI matches its Crossref record; 162 of the 162 references it cites were found in a registry or an index.
Neural development, cell-cell signaling, and the “two-hit” hypothesis of schizophrenia
Abstract
To account for the complex genetics, the developmental biology, and the late adolescent/early adulthood onset of schizophrenia, the "two-hit" hypothesis has gained increasing attention. In this model, genetic or environmental factors disrupt early central nervous system (CNS) development. These early disruptions produce long-term vulnerability to a "second hit" that then leads to the onset of schizophrenia symptoms. The cell-cell signaling pathways involved in nonaxial induction, morphogenesis, and differentiation in the brain, as well as in the limbs and face, could be targets for a "first hit" during early development. These same pathways, redeployed for neuronal maintenance rather than morphogenesis, may be targets for a "second hit" in the adolescent or adult brain. Furthermore, dysregulation of cell-cell signaling by a "first hit" may prime the CNS for a pathologic response to a "second hit" via the same signaling pathway. Thus, parallel disruption of cell-cell signaling in both the developing and the mature CNS provides a plausible way of integrating genetic, developmental, and environmental factors that contribute to vulnerability and pathogenesis in schizophrenia.
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“These studies support a “two hit” model in which ELS, such as maternal separation, confers vulnerability to symptoms of psychiatric illness, but with symptom onset only occurring after exposure to a subsequent stressor (Bayer et al., 1999; Maynard et al., 2001).”
From The effects of early life stress on reward processing (2018) · cites this paper as Maynard et al., 2001
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Steen, R. G., Mull, C., Mcclure, R., Hamer, R. M., & Lieberman, J. A. (2006) · British Journal of Psychiatry · doi:10.1192/bjp.188.6.510 · Cited by 832
Self-citationEarly-life programming of later-life brain and behavior: a critical role for the immune system
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Prenatal Poly(I:C) Exposure and Other Developmental Immune Activation Models in Rodent Systems
Meyer, U. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.07.011 · Cited by 626
The immune system and developmental programming of brain and behavior
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Metadata
- Authors
- Maynard, T. M., Sikich, L., Lieberman, J. A., & LaMantia, A.-S.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- LaMantia, A.-S.
- Venue
- Schizophrenia Bulletin
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-01-01
- Volume
- 27
- Issue
- 3
- Pages
- 457-476
- ISSN
- 0586-7614 (ISSN-L)
- 1745-1701
- OpenAlex
- W2056370816
- Cited by
- 383
- References
- 160
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 18 · 2023: 22 · 2022: 22 · 2021: 29 · 2020: 20 · 2019: 16 · 2018: 19 · 2017: 22 · 2016: 18 · 2015: 17 · 2014: 29 · 2013: 24 · 2012: 20
- FWCI
- 2.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Schizophrenia Bulletin (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH 33127)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-29178)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
- Keywords
- schizophrenia, two-hit hypothesis
- MeSH terms
- Brain, Cell Communication, Chromosome Deletion, Chromosomes, Human, Pair 22, Environment, Humans, Neural Pathways, Psychological Theory, Schizophrenia, Tretinoin
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