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.