Increased brain VDAC1 protein levels correlate with behavioural performance in a ketamine murine model of schizophrenia and are attenuated by the mGluR2 modulator JNJ-46356479.
David Olivares-berjaga, Natàlia Rodríguez, Albert Martínez-pinteño, Laura Rubio-unguetti, Eduard Parellada, Patricia Gassó, Constanza Morén
Schizophrenia research June 16, 2026 Peer reviewed DOI: 10.1016/j.schres.2026.06.010 via PubMed
Summary
In a murine model of schizophrenia, VDAC1 protein levels were found to be significantly increased in the prefrontal cortex (PFC) of ketamine-exposed mice. Treatment with the metabotropic glutamate receptor modulator JNJ-46356479 partially normalized these levels. Additionally, higher VDAC1 levels correlated with an increased Bax/Bcl-2 ratio and poorer cognitive and social performance. These results suggest that VDAC1 may serve as a marker for apoptotic imbalance in schizophrenia and that glutamatergic modulation could provide new therapeutic options.
Study at a glance
| Population | Male and Female C57BL/6 J mice exposed to ketamine or saline |
|---|---|
| Key finding | VDAC1 levels were significantly increased in the PFC of ketamine-exposed mice and partially normalized by JNJ treatment. |
Abstract
Schizophrenia (SZ) is a neurodevelopmental disorder involving excitatory/inhibitory imbalance and apoptotic dysregulation. VDAC1, a voltage-dependent anion channel protein located in the mitochondrial outer membrane, plays a pivotal role in mitochondria-mediated apoptosis. However, its involvement in SZ remains underexplored. This study aimed to investigate VDAC1 protein levels in the prefrontal cortex (PFC) and hippocampus (HPC) of a postnatal ketamine-exposed mouse model of SZ, and to assess the effects of treatment with the metabotropic GLU receptor 2 (mGluR2) positive allosteric modulator JNJ-46356479 (JNJ). We also examined associations between VDAC1 expression, behavioural performance, and other apoptosis-related markers. Male and Female C57BL/6 J mice were exposed to ketamine or saline on postnatal days (PND) 7, 9, and 11, and treated in adulthood with JNJ or vehicle. VDAC1 protein levels in the PFC and HPC were quantified by western blot. Previously acquired behavioural data and levels of apoptotic markers (Bax, Bcl-2, caspase-3) from the same animals were analysed in relation to VDAC1 expression. VDAC1 levels were significantly increased in the PFC of ketamine-exposed mice and partially normalised by JNJ treatment. VDAC1 levels in the PFC and HPC were positively correlated. Higher VDAC1 levels were associated with an increased Bax/Bcl-2 ratio and poorer cognitive and social performance, particularly in the Y-Maze and the Five-Trial Social Memory Tests. Our findings support VDAC1 as a potential molecular marker of apoptotic imbalance in SZ. JNJ treatment may exert neuroprotective effects by modulating VDAC1 levels, suggesting that glutamatergic modulation could offer novel therapeutic avenues targeting mitochondrial dysfunction in SZ.