Cited by 383Schizophrenia research and treatmentNeurotransmitter Receptor Influence on BehaviorMental Health and Psychiatry

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Neural development, cell-cell signaling, and the “two-hit” hypothesis of schizophrenia

Maynard, T. M., Sikich, L., Lieberman, J. A., LaMantia, A.-S.·2001·Schizophrenia Bulletin

DOI 10.1093/oxfordjournals.schbul.a006887

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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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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.
ORCID: Maynard, T. M.
Sikich, L.
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
DOI: 10.1093/oxfordjournals.schbul.a006887
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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Neural development, cell-cell signaling, and the “two-hit” hypothesis of schizophrenia

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