Reversal of behavioral deficits and synaptic dysfunction in mice overexpressing neuregulin 1

Neuron. 2013 May 22;78(4):644-57. doi: 10.1016/j.neuron.2013.03.028.


Neuregulin 1 (Nrg1) is a susceptibility gene of schizophrenia, a disabling mental illness that affects 1% of the general population. Here, we show that ctoNrg1 mice, which mimic high levels of NRG1 observed in forebrain regions of schizophrenic patients, exhibit behavioral deficits and hypofunction of glutamatergic and GABAergic pathways. Intriguingly, these deficits were diminished when NRG1 expression returned to normal in adult mice, suggesting that damage which occurred during development is recoverable. Conversely, increase of NRG1 in adulthood was sufficient to cause glutamatergic impairment and behavioral deficits. We found that the glutamatergic impairment by NRG1 overexpression required LIM domain kinase 1 (LIMK1), which was activated in mutant mice, identifying a pathological mechanism. These observations demonstrate that synaptic dysfunction and behavioral deficits in ctoNrg1 mice require continuous NRG1 abnormality in adulthood, suggesting that relevant schizophrenia may benefit from therapeutic intervention to restore NRG1 signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology
  • Genetic Predisposition to Disease
  • Glutamic Acid / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Neurologic Mutants
  • Mice, Transgenic
  • Neuregulin-1 / genetics
  • Neuregulin-1 / metabolism*
  • Neurons / metabolism
  • Prosencephalon / cytology
  • Prosencephalon / growth & development
  • Prosencephalon / metabolism*
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism
  • Synaptic Transmission / genetics*
  • Synaptic Transmission / physiology
  • Tissue Distribution


  • Neuregulin-1
  • Glutamic Acid