Ablation of ErbB4 from excitatory neurons leads to reduced dendritic spine density in mouse prefrontal cortex

ABSTRACT Dendritic spine loss is observed in many psychiatric disorders, including schizophrenia, and likely contributes to the altered sense of reality, disruption of working memory, and attention deficits that characterize these disorders. ErbB4, a member of the EGF family of receptor tyrosine kinases, is genetically associated with schizophrenia, suggesting that alterations in ErbB4 function contribute to the disease pathology. Additionally, ErbB4 functions in synaptic plasticity, leading us to hypothesize that disruption of ErbB4 signaling may affect dendritic spine development. We show that dendritic spine density is reduced in the dorsomedial prefrontal cortex of ErbB4 conditional whole‐brain knockout mice. We find that ErbB4 localizes to dendritic spines of excitatory neurons in cortical neuronal cultures and is present in synaptic plasma membrane preparations. Finally, we demonstrate that selective ablation of ErbB4 from excitatory neurons leads to a decrease in the proportion of mature spines and an overall reduction in dendritic spine density in the prefrontal cortex of weanling (P21) mice that persists at 2 months of age. These results suggest that ErbB4 signaling in excitatory pyramidal cells is critical for the proper formation and maintenance of dendritic spines in excitatory pyramidal cells. J. Comp. Neurol. 522:3351–3362, 2014. © 2014 Wiley Periodicals, Inc. ErbB4 is a receptor tyrosine kinase known to be associated with schizophrenia in genetic linkage studies. Using a conditional ErbB4 knockout mouse, the authors show that dendritic spine density is reduced in the prefrontal cortex and that ErbB4 can regulate dendritic spine development in excitatory neurons.