Journal 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

Wang, Ziying, Ma, Xianda, Ding, Ying, Khan, Abdul Aziz, Yang, Jiarun, Chen, Lei, Zhang, Xu, Suzuki, Tatsuo, Wang, Shuai, Kuang, Yifang, Li, Weidong, Zhao, Qian, Li, Yuting, Rehman, Zainab, Ye, Jun, Lan, Zhaohui

2025

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Amino Acid Motifs / Amygdala / Animals / Behavior / Behavior, Animal / Biomedical and Life Sciences / Biomedicine / C-Terminus / Conformation / Disease Models, Animal / Disks Large Homolog 4 Protein - metabolism / ErbB-2 protein / ErbB4 / ErbB4-PSD-95-association / Females / Genes / Glutamate receptors / Information processing / Kinases / Laboratory animals / Medical research / Medicine, Experimental / Mental disorders / Mice / Mice, Mutant Strains / Mutant-mouse / Mutants / Mutation / Mutation - genetics / N-Methyl-D-aspartic acid receptors / Neurology / Neurosciences / NMDAR2A hypofunction / Postsynaptic density proteins / Protein Binding / PSD-95 / Psychopharmacology / Receptor, ErbB-4 - chemistry / Receptor, ErbB-4 - genetics / Receptor, ErbB-4 - metabolism / Receptors, N-Methyl-D-Aspartate - metabolism / Schizophrenia / Schizophrenia - genetics / Schizophrenia - physiopathology / Sensory integration / Software / Valine