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Cited by 108Schizophrenia research and treatmentTryptophan and brain disordersNeurotransmitter Receptor Influence on Behavior

The DOI matches its Crossref record; 271 of the 271 references it cites were found in a registry or an index.

Tracing the development of psychosis and its prevention: What can be learned from animal models

Piontkewitz, Yael, Arad, Michal, Weiner, Ina·2012·Neuropharmacology
DOI 10.1016/j.neuropharm.2011.04.019
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Abstract

Schizophrenia (SCZ) is a neurodevelopmental disorder manifested symptomatically after puberty whose pharmacotherapy remains unsatisfactory. In recent years, longitudinal structural neuroimaging studies have revealed that neuroanatomical aberrations occur in this disorder and in fact precede symptom onset, raising the exciting possibility that SCZ can be prevented. There is some evidence that treatment with atypical antipsychotic drugs (APDs) prior to the development of the full clinical phenotype reduces the risk of transition to psychosis, but results remain controversial. It remains unknown whether progressive structural brain aberrations can be halted. Given the diagnostic, ethical, clinical and methodological problems of pharmacological and imaging studies in patients, getting such information remains a major challenge. Animal neurodevelopmental models of SCZ are invaluable for investigating such questions because they capture the notion that the effects of early brain damage are progressive. In recent years, data derived from such models have converged on key neuropathological and behavioral deficits documented in SCZ attesting to their strong validity, and making them ideal tools for evaluating progression of pathology following in-utero insults as well as its prevention. We review here our recent studies that use longitudinal in vivo structural imaging to achieve this aim in the prenatal immune stimulation model that is based on the association of prenatal infection and increased risk for SCZ. Pregnant rats were injected on gestational day 15 with the viral mimic polyriboinosinic-polyribocytidylic acid (poly I:C) or saline. Male and female offspring were imaged and tested behaviorally on postnatal days (PNDs) 35, 46, 56, 70 and 90. In other experiments, offspring of poly I:C- and saline-treated dams received the atypical antipsychotic drugs (APDs) clozapine or risperidone in two developmental windows: PND 34-47 and PND 48-61, and underwent behavioral testing and imaging at adulthood. Prenatal poly I:C-induced interference with fetal brain development led to aberrant postnatal brain development as manifested in structural abnormalities in the hippocampus, the striatum, the prefrontal cortex and lateral ventricles (LV), as seen in SCZ. The specific trajectories were region-, age- and sex-specific, with females having delayed onset of pathology compared to males. Brain pathology was accompanied by development of behavioral abnormalities phenotypic of SCZ, attentional deficit and hypersensitivity to amphetamine, with same sex difference. Hippocampal volume loss and LV volume expansion as well as behavioral abnormalities were prevented in the offspring of poly I:C mothers who received clozapine or risperidone during the asymptomatic period of adolescence (PND 34-47). Administration at a later window, PNDs 48-61, exerted sex-, region- and drug- specific effects. Our data show that prenatal insult leads to progressive postnatal brain pathology, which gradually gives rise to "symptoms"; that treatment with atypical APDs can prevent both brain and behavioral pathology; and that the earlier the intervention, the more pathological outcomes can be prevented.

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Metadata

Authors
Piontkewitz, Y., Arad, M., & Weiner, I.
Affiliations
Tel Aviv University (IL)
Corresponding author
Weiner, Ina
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2012-03
Volume
62
Issue
3
Pages
1273-1289
ISSN
0028-3908 (ISSN-L)
DOI
10.1016/j.neuropharm.2011.04.019
OpenAlex
W1979322945
Cited by
108
References
271
Citations by year
2026: 2 · 2025: 2 · 2023: 5 · 2022: 7 · 2021: 9 · 2020: 8 · 2019: 7 · 2018: 15 · 2017: 7 · 2016: 12 · 2015: 11 · 2014: 9 · 2013: 5 · 2012: 7
FWCI
0.96
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neuropharmacology (publishedVersion)
  • PubMed (publishedVersion)
Funders
United States-Israel Binational Science Foundation (BSF 2007188)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
schizophrenia, neurodevelopmental model, poly(I:C), atypical antipsychotics, clozapine, risperidone, psychosis prevention, hippocampal atrophy, lateral ventricle enlargement, sex differences, attention deficits, prenatal infection, structural neuroimaging, longitudinal brain development, striatum, prefrontal cortex
MeSH terms
Age Factors, Animals, Disease Models, Animal, Female, Hippocampus, Humans, Male, Pregnancy, Prenatal Exposure Delayed Effects, Psychotic Disorders, Early Diagnosis, Rats

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