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Published on: May 23, 2013
Olanzapine enhances early brain maturation through activation of the NODAL/FOXH1 axis
Ziwei Teng1,2, Zhuohui Chen1,3, Tianxiang Zou1
1Department of Psychiatry, National Clinical Research Center for Mental Disorders, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
Abstract:
The portrayed effects of olanzapine on brain development and neuronal response remain unclear under the genetic background of Homo sapiens. Here, we constructed therapeutic-dosage olanzapine-treated cerebral organoid (CO) models using induced pluripotent stem cells from human samples. We found that the activation of NODAL/FOXH1 axis mediated the early response to olanzapine up to day 15, which subsequently caused thicker cortical-like structures, cell identity maturation, higher stemness of neural progenitor cells (NPCs), and mature neuronal firing of early neurons in day 24. Transcriptomics and targeted metabolomics confirmed the upregulation of neurodevelopmental-related terms and glutamate production on day 24. Gene enrichment of transcriptomics into large-scale genome-wide association studies (GWAS) showed possible relationships with intelligence, major depressive disorder, schizophrenia. We did not observe the negative effects of in-utero exposure to olanzapine in mice. Collectively, we tended to conclude that olanzapine treatment had beneficial effects instead of harmful on early brain development.
Insights
Olanzapine treatment may benefit early brain development in humans. Cerebral organoids showed enhanced neuronal maturation and thicker cortical structures, with no observed negative effects in mice.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- The effects of olanzapine on human brain development are not fully understood.
- Investigating olanzapine's impact on neuronal response and brain structure is crucial.
Purpose of the Study:
- To investigate the effects of therapeutic-dosage olanzapine on human cerebral organoids.
- To elucidate the molecular mechanisms underlying olanzapine's impact on early neurodevelopment.
Main Methods:
- Constructed human cerebral organoid (CO) models using induced pluripotent stem cells.
- Analyzed COs treated with olanzapine at therapeutic dosages up to day 24.
- Utilized transcriptomics and targeted metabolomics for molecular analysis.
- Performed gene enrichment analysis with genome-wide association studies (GWAS).
- Assessed effects of in-utero exposure in mouse models.
Main Results:
- Olanzapine activated the NODAL/FOXH1 axis in early development (up to day 15).
- Observed thicker cortical-like structures, mature cell identities, and enhanced neural progenitor cell stemness by day 24.
- Confirmed upregulation of neurodevelopmental pathways and glutamate production.
- GWAS revealed potential links to intelligence, major depressive disorder, and schizophrenia.
- No adverse effects were noted from in-utero exposure in mice.
Conclusions:
- Olanzapine treatment demonstrated potentially beneficial effects on early human brain development in vitro.
- The findings suggest a complex role for olanzapine, potentially promoting neuronal maturation and structure.
- Further research is warranted to explore these beneficial effects and their clinical implications.
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