Effects of JNJ-46356479 and clozapine on VGLUT1 and GAD65/67 brain levels and expression of genes related to glutamate and GABA in mice postnatally exposed to ketamine.

Abstract

Schizophrenia (SZ) is a complex mental disorder influenced by genetic, environmental, and neurobiological factors, with current treatments ineffective for negative symptoms and cognitive deficits. The glutamatergic hypothesis of SZ highlights the N-methyl-D-aspartic acid (NMDA) receptor dysfunction as a key factor, causing excitatory-inhibitory imbalance and synaptic inefficiency. Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2), such as JNJ-46356479 (JNJ), could be useful in treating these symptoms, especially when used in early stages of the disease. Previous results have shown that JNJ can reverse certain SZ-related behavioral and neuropathological deficits. This study evaluates, for the first time, the effects of early treatment with JNJ or clozapine (CLZ) in reversing molecular deficits related to glutamatergic and GABAergic pathways in mice postnataly exposed to ketamine (KET) on postnatal days (PND) 7, 9, and 11. Animals received JNJ or CLZ daily in the adolescent period (PND 35-60). Specifically, we investigated alterations in brain protein levels of VGLUT1, as a marker of glutamatergic synapses, and GAD65/67, as markers of GABAergic synapses. Changes in brain expression of 240 selected genes involved in glutamate and GABA pathways were also evaluated. Results demonstrated that postnatal KET exposure increased hippocampal VGLUT1 levels which were partially normalized after both pharmacological treatments, especially with JNJ. Additionally, we identified some genes that showed altered brain expression after drug treatment in our mouse model. In conclusion, this study provides evidence of SZ-related glutamate signaling alterations in adult mice postnatally exposed to KET, as well as of the effectiveness of JNJ in improving these alterations when administered during the early stages of the disease.