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Keywords:

  • environmental enrichment;
  • ERBB4;
  • NRG1;
  • plasticity;
  • schizophrenia;
  • synapse

Abstract

Thumbnail image of graphical abstract

The biological functions of the neuregulin 1 (NRG1) and ERBB4 genes have received much recent attention due to several studies showing associations between these genes and schizophrenia. Moreover, reduced forebrain dendritic spine density is a consistent feature of schizophrenia. It is thus important to understand the mechanisms whereby NRG1 and erbB4 modulate spine morphogenesis. Here, we show that long-term incubation with NRG1 increases both spine size and density in cortical pyramidal neurons. NRG1 also enhances the content of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors in spines. Knockdown of ERBB4 expression prevented the effects of NRG1 on spine size, but not on spine density. The effects of NRG1 and erbB4 on spines were mediated by the RacGEF kalirin, a well-characterized regulator of dendritic spines. Finally, we show that environmental enrichment, known to promote spine growth, robustly enhances the levels of erbB4 protein in the forebrain. These findings provide a mechanistic link between NRG1 signaling and spine morphogenesis.

NRG1 and erbB4 increase spine size, while NRG1 activity, but not erbB4 activity, increases spine density. NRG1 also increases spine GluA1 content, and the GEF kalirin is necessary for the ability of NRG1 and erbB4 to regulate spine morphogenesis. We find that environmental enrichment, which is known to stimulate spine morphogenesis in the forebrain, increases cortical and hippocampal erbB4 expression.