Olanzapine enhances early brain maturation through activation of the NODAL/FOXH1 axis

Ziwei Teng; Zhuohui Chen; Tianxiang Zou; Yuhan Su; Hongtao Zeng; Shixiong Sun; Haiyu Chen; Jieyu Liu; Yue Qin; Haishan Wu; Jindong Chen; Fangkun Liu; Renrong Wu; Jing Huang

doi:10.1016/j.isci.2024.110917

Olanzapine enhances early brain maturation through activation of the NODAL/FOXH1 axis

iScience. 2024 Sep 11;27(10):110917. doi: 10.1016/j.isci.2024.110917. eCollection 2024 Oct 18.

Authors

Ziwei Teng^{1

2}, Zhuohui Chen^{1

3}, Tianxiang Zou¹, Yuhan Su¹, Hongtao Zeng¹, Shixiong Sun¹, Haiyu Chen¹, Jieyu Liu⁴, Yue Qin¹, Haishan Wu¹, Jindong Chen¹, Fangkun Liu³, Renrong Wu¹, Jing Huang¹

Affiliations

¹ Department 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.
² Department of Psychiatry, Clinical Research Center for Depressive Disorder in Hunan Province, The Second People's Hospital of Hunan Province (Brain Hospital of Hunan Province), Changsha 410007, China.
³ Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, China.
⁴ Department of Ultrasound Diagnosis, 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.

Keywords: Biological sciences; Cellular neuroscience; Developmental neuroscience; Natural sciences; Neuroscience.