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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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Maynard, T. M., Haskell, G., Lieberman, J. A., & LaMantia, A. (2002) · International Journal of Developmental Neuroscience · doi:10.1016/s0736-5748(02)00050-3 · Cited by 47
Self-citationCookey, J., Bernier, D. C., & Tibbo, P. G. (2014) · Schizophrenia Research · doi:10.1016/j.schres.2014.04.026 · Cited by 45
Depth of the olfactory sulcus: A marker of early embryonic disruption in schizophrenia?
Turetsky, B. I., Crutchley, P., Walker, J., Gur, R. E., & Moberg, P. J. (2009) · Schizophrenia Research · doi:10.1016/j.schres.2009.09.005 · Cited by 45
Does cannabidiol have a role in the treatment of schizophrenia?
Gururajan, A., & Malone, D. T. (2016) · Schizophrenia Research · doi:10.1016/j.schres.2016.06.022 · Cited by 51
Maternal Diabetes and Fetal Programming Toward Neurological Diseases: Beyond Neural Tube Defects
Márquez‐Valadez, B., Valle-Bautista, R., García-López, G., Díaz, N. F., & Molina‐Hernández, A. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00664 · Cited by 47
Early life stress and psychiatric disorder modulate cortical responses to affective stimuli
Weber, K., Miller, G. A., Schupp, H. T., Borgelt, J., Awiszus, B., Popov, T. G., Elbert, T. R., & Rockstroh, B. S. (2009) · Psychophysiology · doi:10.1111/j.1469-8986.2009.00871.x · Cited by 43
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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