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

J Comp Neurol. 2014 Oct 1;522(14):3351-62. doi: 10.1002/cne.23615. Epub 2014 Apr 29.

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.

Keywords: layer V; neuregulin; neurodevelopment; receptor tyrosine kinase; schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cell Fractionation
  • Cells, Cultured
  • Dendritic Spines / metabolism
  • Dendritic Spines / physiology*
  • Disks Large Homolog 4 Protein
  • Gene Expression Regulation / genetics*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Guanylate Kinases / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Nestin / genetics
  • Nestin / metabolism
  • Neurons / metabolism
  • Neurons / ultrastructure*
  • Prefrontal Cortex / cytology*
  • Prefrontal Cortex / embryology
  • Prefrontal Cortex / growth & development
  • Receptor, ErbB-4 / deficiency*
  • Receptor, ErbB-4 / genetics
  • Synapses / metabolism
  • Transfection

Substances

  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Membrane Proteins
  • Nes protein, mouse
  • Nestin
  • Green Fluorescent Proteins
  • Erbb4 protein, mouse
  • Receptor, ErbB-4
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Mitogen-Activated Protein Kinase 3
  • Guanylate Kinases