Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes

Neuron. 2013 Sep 18;79(6):1152-68. doi: 10.1016/j.neuron.2013.07.010.

Abstract

Genetic variation in neuregulin and its ErbB4 receptor has been linked to schizophrenia, although little is known about how they contribute to the disease process. Here, we have examined conditional Erbb4 mouse mutants to study how disruption of specific inhibitory circuits in the cerebral cortex may cause large-scale functional deficits. We found that deletion of ErbB4 from the two main classes of fast-spiking interneurons, chandelier and basket cells, causes relatively subtle but consistent synaptic defects. Surprisingly, these relatively small wiring abnormalities boost cortical excitability, increase oscillatory activity, and disrupt synchrony across cortical regions. These functional deficits are associated with increased locomotor activity, abnormal emotional responses, and impaired social behavior and cognitive function. Our results reinforce the view that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / genetics*
  • Action Potentials / physiology
  • Animals
  • Animals, Newborn
  • Brain / pathology*
  • Brain / physiopathology
  • Cognition Disorders / etiology
  • Cognition Disorders / genetics
  • Disease Models, Animal
  • Electroporation
  • ErbB Receptors / deficiency*
  • ErbB Receptors / genetics
  • Glutamate Decarboxylase / metabolism
  • Green Fluorescent Proteins / genetics
  • In Vitro Techniques
  • Interneurons / physiology*
  • LIM-Homeodomain Proteins / genetics
  • Male
  • Maze Learning / physiology
  • Mice
  • Mice, Transgenic
  • Motor Activity / genetics
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Parvalbumins / metabolism
  • Patch-Clamp Techniques
  • Phenotype*
  • Proteins / genetics
  • Proteins / metabolism
  • RNA, Untranslated
  • Receptor, ErbB-4
  • Receptors, GABA-A / metabolism
  • Schizophrenia* / complications
  • Schizophrenia* / genetics
  • Schizophrenia* / pathology
  • Social Behavior
  • Statistics as Topic
  • Synaptic Transmission / genetics
  • Transcription Factors / genetics

Substances

  • Gt(ROSA)26Sor non-coding RNA, mouse
  • LHX6 protein, mouse
  • LIM-Homeodomain Proteins
  • Nerve Tissue Proteins
  • Parvalbumins
  • Proteins
  • RNA, Untranslated
  • Receptors, GABA-A
  • Transcription Factors
  • Green Fluorescent Proteins
  • ErbB Receptors
  • Erbb4 protein, mouse
  • Receptor, ErbB-4
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2