Exploration of schizophrenia-related behavioral and molecular abnormalities in a mutant mouse model with a mutation in the TVV motif of the ErbB4 gene

The ErbB4 gene is a schizophrenia (SCZ) risk gene that interacts with PSD-95 via its C-terminus, a connection disrupted in SCZ patients. To investigate the functional significance of this interaction, we generated a zygotic mutant mouse lacking the terminal valine "V" residue from the ErbB4 TVV motif. The homozygous (homo) mice exhibited disrupted ErbB4‒PSD-95 interactions and SCZ-relevant behavioral deficits, including impairments in motor function, sensory processing, and memory performance. Structural computational analysis further revealed that the mutation altered the structural conformation of the ErbB4 C-terminus, which affected its binding affinity for PSD-95. Mechanistically, the mutation led to up-regulated but less activation of ErbB4 and down-regulated but overactivation of PSD-95, possibly representing a failed compensatory response aiming to maintain the ErbB4-PSD-95 interaction. Additionally, homo mice presented NMDAR2A subunit specific hypofunction and reduced GAD67 expression. These findings highlight that the ErbB4-PSD-95 interaction is a critical molecular link in the synaptic dysfunction and behavioral abnormalities associated with SCZ.

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Publication Details

Journal
Molecular Brain
Published
2025-10-09
DOI
https://doi.org/10.1186/s13041-025-01238-2
Primary Topic
Receptor Mechanisms and Signaling
Type
article
Field-Weighted Citation Impact
0.00

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article

Exploration of schizophrenia-related behavioral and molecular abnormalities in a mutant mouse model with a mutation in the TVV motif of the ErbB4 gene

Tatsuo Suzuki, Abdul Aziz Khan, Yifang Kuang, Y. Li et al.
Molecular Brain
Receptor Mechanisms and Signaling
article

Exploration of schizophrenia-related behavioral and molecular abnormalities in a mutant mouse model with a mutation in the TVV motif of the ErbB4 gene

Tatsuo Suzuki, Abdul Aziz Khan, Yifang Kuang, Y. Li, Xianda Ma, Zainab Rehman, Jiarun Yang, Qian Zhao, Ying Ding, Shuai Wang, Wei Li, Jun Ye, Xu Zhang, Leilei Chen, Z. Lan, Ziying Wang
article en

Abstract

The ErbB4 gene is a schizophrenia (SCZ) risk gene that interacts with PSD-95 via its C-terminus, a connection disrupted in SCZ patients. To investigate the functional significance of this interaction, we generated a zygotic mutant mouse lacking the terminal valine "V" residue from the ErbB4 TVV motif. The homozygous (homo) mice exhibited disrupted ErbB4‒PSD-95 interactions and SCZ-relevant behavioral deficits, including impairments in motor function, sensory processing, and memory performance. Structural computational analysis further revealed that the mutation altered the structural conformation of the ErbB4 C-terminus, which affected its binding affinity for PSD-95. Mechanistically, the mutation led to up-regulated but less activation of ErbB4 and down-regulated but overactivation of PSD-95, possibly representing a failed compensatory response aiming to maintain the ErbB4-PSD-95 interaction. Additionally, homo mice presented NMDAR2A subunit specific hypofunction and reduced GAD67 expression. These findings highlight that the ErbB4-PSD-95 interaction is a critical molecular link in the synaptic dysfunction and behavioral abnormalities associated with SCZ.

Molecular BrainVol. 18(1)
Shinshu University (JP), Ministry of Science and Technology (VN), Western Digital (China) (CN), USF Health Byrd Alzheimer's Institute (US)
China Postdoctoral Science Foundation, Shanghai Municipal Education Commission, China Scholarship Council, Abdul Wali Khan University Mardan, Shanghai Jiao Tong University, Natural Science Foundation of Chongqing, Program of Shanghai Subject Chief Scientist, Centre Scientifique et Technique du Bâtiment, National Science Fund for Distinguished Young Scholars
Openalex Percentile: Top 75%
Receptor Mechanisms and Signaling
DOIOpen Access PDFOpenAlex
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