2026 ECNP Congress

PS02-2017

Chronic treatment with the mGluR2 positive allosteric modulator JNJ-46356479 attenuates apoptosis-related alterations in adulthood in a postnatal-ketamine model of schizophrenia

David Olivares Berjaga — A. Martinez-Pinteño, N. Rodriguez, L. Rubio-Unguetti, C. Cañete, N. Guasch, G. Mezquida, E. Parellada, P. Gassó · Universitat de Barcelona, Basic Clinical Practice, Barcelona, Spain

2026 ECNP Congress

The glutamatergic hypothesis of schizophrenia states that dysregulation of glutamatergic neurotransmission, particularly an increase in extracellular glutamate levels, can trigger excitotoxic processes and promote aberrant synaptic pruning through the activation of apoptotic pathways in dendritic spines [1]. This mechanism is thought to contribute to long-term structural and functional alterations in brain regions critically involved in the disorder, such as the prefrontal cortex (PFC) and the hippocampus (HPC) [2]. In line with this hypothesis, alterations in key markers of apoptosis have been consistently reported both in patients with schizophrenia and in relevant animal models, suggesting a shift towards a pro-apoptotic state that may underlie synaptic dysfunction and behavioral impairments [3].

Among potential therapeutic strategies, positive allosteric modulators (PAMs) of metabotropic glutamate receptor 2 (mGluR2), such as JNJ-46356479 (JNJ), have emerged as promising candidates due to their ability to reduce presynaptic glutamate release and restore glutamatergic balance [4]. Given the importance of early interventions during critical neurodevelopmental windows, the present study aimed to evaluate whether sustained pharmacological treatment from adolescence to adulthood with JNJ, in comparison with clozapine (CLZ), modulates the levels of the apoptosis-related proteins (caspase-3, Bax, and Bcl-2) in the PFC and HPC using a postnatal ketamine-exposed mouse model of schizophrenia. Additionally, we explored the relationship between these molecular changes and selected behavioral alterations.

To this end, mice were exposed to ketamine on postnatal days (PND) 7, 9, and 11, a well-established protocol to induce schizophrenia-like phenotypes. From adolescence (PND 35), animals received daily administration of JNJ (10 mg/kg), CLZ (10 mg/kg), or vehicle, and treatment was maintained until adulthood (PND 120). At this stage, PFC and HPC tissues were collected, and protein levels of caspase-3, Bax, and Bcl-2 were quantified by Western blotting. Furthermore, correlational analyses were conducted to examine the association between apoptotic markers and selected behavioral outcomes, including social memory performance and anxiety-like behavior.

Postnatal exposure to ketamine resulted in a significant reduction of the anti-apoptotic protein Bcl-2 and an increase in the Bax/Bcl-2 ratio in the PFC, indicating a shift towards a pro-apoptotic profile. Notably, maintained treatment with either JNJ or CLZ effectively reversed these alterations, restoring Bcl-2 levels and normalizing the Bax/Bcl-2 balance in the PFC. Correlational analyses revealed that Bax and the Bax/Bcl-2 ratio in the PFC were positively associated with interaction time in trial 4 of the 5-trial social memory test, reflecting impaired habituation processes. In addition, caspase-3 levels in the PFC and the Bax/Bcl-2 ratio in the HPC were negatively correlated with time spent in the center of the open field test, suggesting a link between apoptotic signaling and increased anxiety-like behavior.

Overall, these findings indicate that adolescent-initiated chronic treatment with JNJ and CLZ attenuates the ketamine-induced pro-apoptotic bias in the PFC and highlights a relationship between regional apoptotic status and specific behavioral alterations. This supports the potential value of sustained interventions targeting glutamatergic circuits during critical periods of neurodevelopment to prevent long-term pathological outcomes associated with schizophrenia.

References

  1. Parellada, E., & Gassó, P. (2021). Glutamate and microglia activation as a driver of dendritic apoptosis: a core pathophysiological mechanism to understand schizophrenia. Translational psychiatry, 11(1), 271. https://doi.org/10.1038/s41398-021-01385-9
  2. Leucht, S., Siafis, S., McGrath, J. J., McGorry, P., Howes, O. D., Tamminga, C., Carr, R., Bighelli, I., Schneider-Thoma, J., Priller, J., & Davis, J. M. (2025). Schizophrenia. Nature reviews. Disease primers, 11(1), 83. https://doi.org/10.1038/s41572-025-00667-6
  3. Morén, C., Treder, N., Martínez-Pinteño, A., Rodríguez, N., Arbelo, N., Madero, S., Gómez, M., Mas, S., Gassó, P., & Parellada, E. (2022). Systematic Review of the Therapeutic Role of Apoptotic Inhibitors in Neurodegeneration and Their Potential Use in Schizophrenia. Antioxidants (Basel, Switzerland), 11(11), 2275. https://doi.org/10.3390/antiox11112275
  4. Olivares-Berjaga, D., Martínez-Pinteño, A., Rodríguez, N., Mas, S., Morén, C., Parellada, E., & Gassó, P. (2025). Effectiveness of positive allosteric modulators of metabotropic glutamate receptor 2/3 (mGluR2/3) in animal models of schizophrenia. Translational psychiatry, 15(1), 11. https://doi.org/10.1038/s41398-024-03194-2