Effects of the PAM of mGluR2, JNJ-46356479, on brain apoptotic protein levels in a mouse model of schizophrenia

Prog Neuropsychopharmacol Biol Psychiatry. 2024 Apr 20:131:110955. doi: 10.1016/j.pnpbp.2024.110955. Epub 2024 Feb 1.


Current treatment for schizophrenia (SZ) ameliorates the positive symptoms, but is inefficient in treating the negative and cognitive symptoms. The SZ glutamatergic dysfunction hypothesis has opened new avenues in the development of novel drugs targeting the glutamate storm, an inducer of progressive neuropathological changes. Positive allosteric modulators of metabotropic glutamate receptor 2 (mGluR2), such as JNJ-46356479 (JNJ), reduce the presynaptic release of glutamate, which has previously been demonstrated to attenuate glutamate- and dopamine-induced apoptosis in human neuroblastoma cell cultures. We hypothesised that JNJ treatment would modify the brain levels of apoptotic proteins in a mouse model of ketamine (KET)-induced schizophrenia. We analysed the levels of proapoptotic (caspase-3 and Bax) and antiapoptotic (Bcl-2) proteins by western blot in the prefrontal cortex and hippocampus of JNJ-treated mice. JNJ attenuated apoptosis in the brain by partially restoring the levels of the antiapoptotic Bcl-2 protein, which is significantly reduced in animals exposed to KET. Additionally, a significant inverse correlation was observed between proapoptotic protein levels and behavioural deficits in the mice. Our findings suggest that JNJ may attenuate brain apoptosis in vivo, as previously described in cell cultures, providing a link between neuropathological deficits and SZ symptomatology.

Keywords: Apoptosis; Ketamine; Metabotropic glutamate receptor modulator; Murine model, JNJ-46356479; Schizophrenia.

MeSH terms

  • Animals
  • Brain / metabolism
  • Glutamates / metabolism
  • Humans
  • Ketamine* / pharmacology
  • Mice
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, Metabotropic Glutamate*
  • Schizophrenia* / chemically induced
  • Schizophrenia* / drug therapy
  • Schizophrenia* / metabolism


  • metabotropic glutamate receptor 2
  • Ketamine
  • Proto-Oncogene Proteins c-bcl-2
  • Glutamates
  • Receptors, Metabotropic Glutamate