Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors

Nat Med. 2011 Apr;17(4):470-8. doi: 10.1038/nm.2315. Epub 2011 Mar 27.


Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1β-ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / metabolism
  • Disease Susceptibility
  • Electric Stimulation
  • ErbB Receptors / metabolism*
  • Excitatory Postsynaptic Potentials
  • Humans
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Neurological
  • Neuregulin-1 / metabolism*
  • Neuregulin-1 / pharmacology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, ErbB-4
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Schizophrenia / etiology*
  • Schizophrenia / metabolism*
  • Signal Transduction
  • src-Family Kinases / metabolism*


  • Neuregulin-1
  • Receptors, N-Methyl-D-Aspartate
  • ERBB4 protein, human
  • ErbB Receptors
  • Erbb4 protein, mouse
  • Erbb4 protein, rat
  • Receptor, ErbB-4
  • src-Family Kinases