Synaptic and cellular changes induced by the schizophrenia susceptibility gene G72 are rescued by N-acetylcysteine treatment

Transl Psychiatry. 2016 May 10;6(5):e807. doi: 10.1038/tp.2016.74.


Genetic studies have linked the primate-specific gene locus G72 to the development of schizophrenia and bipolar disorder. Transgenic mice carrying the entire gene locus express G72 mRNA in dentate gyrus (DG) and entorhinal cortex, causing altered electrophysiological properties of their connections. These transgenic mice exhibit behavioral alterations related to psychiatric diseases, including cognitive deficits that can be reversed by treatment with N-acetylcysteine, which was also found to be effective in human patients. Here, we show that G72 transgenic mice have larger excitatory synapses with an increased amount of N-methyl-d-aspartate (NMDA) receptors in the molecular layer of DG, compared with wild-type littermates. Furthermore, transgenic animals have lower number of dentate granule cells with a parallel, but an even stronger decrease in the number of excitatory synapses in the molecular layer. Importantly, we also show that treatment with N-acetylcysteine can effectively normalize all these changes in transgenic animals, resulting in a state similar to wild-type mice. Our results show that G72 transcripts induce robust alterations in the glutamatergic system at the synaptic level that can be rescued with N-acetylcysteine treatment.

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Carrier Proteins / genetics*
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / metabolism*
  • Dentate Gyrus / physiopathology
  • Entorhinal Cortex / drug effects
  • Entorhinal Cortex / metabolism*
  • Entorhinal Cortex / physiopathology
  • Free Radical Scavengers / pharmacology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Transgenic
  • RNA, Messenger / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism
  • Synapses / metabolism


  • Carrier Proteins
  • DAOA protein, human
  • Free Radical Scavengers
  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Receptors, N-Methyl-D-Aspartate
  • Acetylcysteine