Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex

Nat Commun. 2015 Dec 11:6:10118. doi: 10.1038/ncomms10118.


Neuregulin-1 (NRG1) and its receptor ErbB4 influence several processes of neurodevelopment, but the mechanisms regulating this signalling in the mature brain are not well known. DISC1 is a multifunctional scaffold protein that mediates many cellular processes. Here we present a functional relationship between DISC1 and NRG1-ErbB4 signalling in mature cortical interneurons. By cell type-specific gene modulation in vitro and in vivo including in a mutant DISC1 mouse model, we demonstrate that DISC1 inhibits NRG1-induced ErbB4 activation and signalling. This effect is likely mediated by competitive inhibition of binding of ErbB4 to PSD95. Finally, we show that interneuronal DISC1 affects NRG1-ErbB4-mediated phenotypes in the fast spiking interneuron-pyramidal neuron circuit. Post-mortem brain analyses and some genetic studies have reported interneuronal deficits and involvement of the DISC1, NRG1 and ErbB4 genes in schizophrenia, respectively. Our results suggest a mechanism by which cross-talk between DISC1 and NRG1-ErbB4 signalling may contribute to these deficits.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cerebral Cortex
  • Humans
  • Interneurons / physiology*
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neuregulin-1 / genetics
  • Neuregulin-1 / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, ErbB-4 / genetics
  • Receptor, ErbB-4 / metabolism*
  • Signal Transduction / physiology
  • Synapses / physiology*


  • Disc1 protein, mouse
  • Nerve Tissue Proteins
  • Neuregulin-1
  • Nrg1 protein, mouse
  • Erbb4 protein, mouse
  • Receptor, ErbB-4