Maintained JNJ-46356479 treatment, a positive allosteric modulator of mGluR2, improved induced cognitive deficits in a schizophrenia postnatally ketamine-exposed mouse model

Positive allosteric modulators of the mGluR2 receptor, such as JNJ-46356479 (JNJ), which act by inhibiting the presynaptic release of glutamate, represent a promising pharmacological strategy for addressing the negative and cognitive symptoms of schizophrenia, domains that are often insufficiently treated by current antipsychotic medications [1]. Previous studies from our group have demonstrated that JNJ administration, when restricted either to adolescence or adulthood, is capable of ameliorating behavioral deficits induced in a mouse model of schizophrenia generated through postnatal exposure to ketamine (KET), an NMDA receptor antagonist [2]. These findings support the relevance of glutamatergic modulation in this experimental model and are consistent with previous evidence highlighting the role of glutamate dysregulation in schizophrenia-related alterations [3]. In the present study, we aimed to determine whether prolonged treatment with JNJ, initiated during adolescence and maintained into adulthood, could preserve or even enhance these beneficial effects. For comparison, we also evaluated clozapine (CLZ), a well-established atypical antipsychotic. C57BL/6J mice were exposed to KET (30 mg/kg) or saline on postnatal days (PND) 7, 9, and 11. Subsequently, from PND 35 to 120, animals received daily treatment with JNJ (10 mg/kg), CLZ (10 mg/kg), or vehicle. Behavioral assessments were conducted in adulthood (starting at PND 90) using a comprehensive battery of tests, including the Open Field Test (OFT), Y-Maze, Novel Object Recognition Test (NORT), Three-Chamber Social Test (3-CHT), and Five-Trial Social Memory Test (5T-SMT). All behavioral tests were performed under standard conditions and analyzed using conventional parameters for each paradigm to ensure consistency and reproducibility across experimental groups. Results showed that prolonged treatment with JNJ and CLZ led to a reduction in locomotor activity in the OFT, reflected by shorter distances traveled and fewer vertical rearing behaviors, which may indicate a mild sedative effect following chronic administration. This effect was observed in both treatment groups compared to their respective controls. In the 5T-SMT, control animals exhibited the expected preference for social novelty, while this response was absent in KET-exposed mice treated with vehicle, suggesting impaired social memory. Remarkably, JNJ-treated animals recovered this preference, demonstrating a restoration of social recognition abilities. Similarly, in the NORT, early exposure to KET was associated with a tendency toward deficits in visual recognition memory. However, this impairment was alleviated by both JNJ and CLZ treatments. No additional differences between treatment groups were detected in this task under the conditions evaluated in this study. Overall, these findings demonstrate that chronic administration of JNJ effectively attenuates behavioral deficits induced by early-life NMDA receptor blockade. Moreover, its effects appear to be equal or superior to those of clozapine, without evidence of tolerance or toxicity. This reinforces the therapeutic potential of targeting glutamatergic signaling, particularly via mGluR2 modulation, as a novel and promising approach for the treatment of schizophrenia. Further studies may help to better characterize the duration and stability of these effects over time as well as to confirm their consistency across different experimental settings.

References

1. 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
2. Olivares-Berjaga, D., Martínez-Pinteño, A., Rodríguez, N., Madero, S., Prohens, L., Martínez-Serrano, I., Mas, S., Morén, C., Parellada, E., & Gassó, P. (2024). Effects of the PAM of mGluR2, JNJ-46356479, on brain apoptotic protein levels in a mouse model of schizophrenia. Progress in neuro-psychopharmacology & biological psychiatry, 131, 110955. https://doi.org/10.1016/j.pnpbp.2024.110955
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