miR143-3p-Mediated NRG-1-Dependent Mitochondrial Dysfunction Contributes to Olanzapine Resistance in Refractory Schizophrenia.

Abstract

BACKGROUND:

Olanzapine is an effective antipsychotic medication for treatment-resistant schizophrenia (TRS); however, the therapeutic effectiveness of olanzapine has been found to vary in individual patients. It is imperative to unravel its resistance mechanisms and find reliable targets to develop novel precise therapeutic strategies.

METHODS:

Unbiased RNA sequencing analysis was performed using homogeneous populations of neural stem cells derived from induced pluripotent stem cells in 3 olanzapine responder (reduction of Positive and Negative Syndrome Scale score ≥25%) and 4 nonresponder (reduction of Positive and Negative Syndrome Scale score <25%) inpatients with TRS. We also used a genotyping study from patients with TRS to assess the candidate genes associated with the olanzapine response. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9-mediated genome editing, neurologic behavioral tests, RNA silencing, and microRNA sequencing were used to investigate the phenotypic mechanisms of an olanzapine resistance gene in patients with TRS.

RESULTS:

Neuregulin-1 (NRG-1) deficiency-induced mitochondrial dysfunction is associated with olanzapine treatment outcomes in TRS. NRG-1 knockout mice showed schizophrenia-relevant behavioral deficits and yielded olanzapine resistance. Notably, miR143-3p is a critical NRG-1 target related to mitochondrial dysfunction, and miR143-3p levels in neural stem cells associate with severity to olanzapine resistance in TRS. Meanwhile, olanzapine resistance in NRG-1 knockout mice could be rescued by treatment with miR143-3p agomir via intracerebral injection.

CONCLUSIONS:

Our findings provide direct evidence of olanzapine resistance resulting from NRG-1 deficiency-induced mitochondrial dysfunction, and they link olanzapine resistance and NRG-1 deficiency-induced mitochondrial dysfunction to an NRG-1/miR143-3p axis, which constitutes a novel biomarker and target for TRS.

• Authors: Jing Sun, Xiaoya Zhang, Qijie Cong, Dong Chen, Zhenghui Yi, Hailiang Huang, Cong Wang, Mo Li, Rongsen Zeng, Yunxi Liu, Cong Huai, Luan Chen, Chuanxin Liu, Yan Zhang, Yong Xu, Lingzi Fan, Guoqiang Wang, Chuanfu Song, Muyun Wei, Huihui Du, Jinhang Zhu, Lin He, Shengying Qin
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 92 Issue 5 Pg. 419-433 (09 01 2022) ISSN: 1873-2402 [Electronic] United States
• PMID: 35662508 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antipsychotic Agents
• Neuregulin-1
• Olanzapine

Topics

• Animals
• Antipsychotic Agents (pharmacology, therapeutic use)
• Humans
• Mice
• Mice, Knockout
• Mitochondria
• Neuregulin-1 (genetics, therapeutic use)
• Olanzapine (therapeutic use)
• Schizophrenia (drug therapy, genetics)
• Schizophrenia, Treatment-Resistant