Loss of Nogo-A, encoded by the schizophrenia risk gene Rtn4, reduces mGlu3 expression and causes hyperexcitability in hippocampal CA3 circuits

PLoS One. 2018 Jul 24;13(7):e0200896. doi: 10.1371/journal.pone.0200896. eCollection 2018.

Abstract

Recent investigations of Nogo-A, a well characterized protein inhibitor of neurite outgrowth in the brain, have revealed additional functions including a role in neuropsychiatric disorders such as schizophrenia. Here we examined Nogo-A functions in mouse CA3 hippocampal circuitry. Patch clamp recordings showed that the absence of Nogo-A results in a hyperactive network. In addition, mGlu3 metabotropic glutamate receptors, which exhibit mutations in certain forms of schizophrenia, were downregulated specifically in the CA3 area. Furthermore, Nogo-A-/- mice showed disordered theta oscillations with decreased incidence and frequency, similar to those observed in mGlu3-/- mice. As disruptions in theta rhythmicity are associated with impaired spatial navigation, we tested mice using modified Morris water maze tasks. Mice lacking Nogo-A exhibited altered search strategies, displaying greater dependence on global as opposed to local reference frames. This link between Nogo-A and mGlu3 receptors may provide new insights into mechanisms underlying schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA3 Region, Hippocampal / pathology
  • CA3 Region, Hippocampal / physiopathology*
  • Down-Regulation / genetics*
  • Gene Deletion
  • Maze Learning
  • Mice
  • Nogo Proteins / deficiency*
  • Nogo Proteins / genetics*
  • Nogo Proteins / metabolism
  • Protein Transport
  • Receptors, Metabotropic Glutamate / genetics*
  • Schizophrenia / genetics*
  • Schizophrenia / pathology
  • Schizophrenia / physiopathology*
  • Spatial Behavior
  • Synapses / genetics
  • Synapses / metabolism

Substances

  • Nogo Proteins
  • Receptors, Metabotropic Glutamate
  • Rtn4 protein, mouse
  • metabotropic glutamate receptor 3

Grants and funding

This study was funded by the Swiss National Science Foundation grant 31003A_143373 / 1 to U.G. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.