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Clozapine induces perineuronal net remodeling in a developmental mouse model exhibiting schizophrenia-relevant phenotypes

Neuropsychopharmacology (2025)Cite this article

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Abstract

Schizophrenia (SCZ) is a multifaceted neurodevelopmental disorder characterized by widespread dysregulation of extracellular matrix (ECM) components, particularly perineuronal nets (PNNs), which are crucial for synaptic stability and cognitive function. Alterations in PNNs, especially in the prefrontal cortex (PFC), have been linked to cognitive deficits in SCZ. While antipsychotic (AP) treatments have been suggested to influence PNNs and ECM integrity, their specific effects remain unclear. In this study, we used a neurodevelopmental mouse model exhibiting SCZ-relevant phenotypes, induced by perinatal NMDA receptor hypofunction through ketamine administration, to investigate the impact of PNN alterations and their modulation by clozapine (CLZ), an atypical AP, in adulthood. We found that ketamine exposure led to increased PNN thickness and reduced structural complexity (i.e., more compact and less porous PNNs), elevated VGLUT1-mediated excitatory inputs, and dysregulated medial PFC network activity, characterized by hyperactivation of surviving PV interneurons and a disrupted excitation/inhibition balance. Treatment with CLZ mitigated these changes by partially restoring PNN microarchitecture and enhancing the structural integrity and porosity of PNNs in the medial PFC. Additionally, CLZ-mediated effects on PNNs were associated with improvements in cognitive flexibility and social memory, functions tightly linked to PFC-dependent processing. These findings suggest that CLZ’s actions on PNN structure may contribute to its therapeutic effects in conditions involving prefrontal cortical dysfunction, as observed in SCZ, although these correlations require further investigation to confirm their causal relevance. Overall, our results underscore the need for further investigation into the impact of AP medications on PNN plasticity and ECM integrity.

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Fig. 1: Ketamine neurodevelopmental model presented alterations in PV interneurons and PNNs during adulthood.
Fig. 2: Clozapine modulated the expression of key ECM components in the PFC of the ketamine neurodevelopmental model.
Fig. 3: Clozapine modulated structural and morphological changes in PNNs surrounding PV interneurons in the mPFC of the ketamine neurodevelopmental model.
Fig. 4: Clozapine induced synaptic changes in PNN-positive PV interneurons.
Fig. 5: Clozapine enhanced cognitive flexibility and improved social memory impairments in the ketamine neurodevelopmental model.

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Data availability

The datasets generated from this study are available upon request to the corresponding authors.

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Acknowledgements

The authors thank Prof. Carmen Martínez-Cue for her critical reading of the manuscript and insightful comments on the behavioral design; Diego García-González and Maurizio Riga for their valuable input and suggestions during lab meetings; Víctor Ramos Herrero for his technical assistance; and, especially, Amanda Moreno Mellado for her outstanding technical support and dedication throughout the project; the staff at the research facilities of the Institute of Biomedicine of Seville (IBiS)-CSIC; Teresa Martínez-Cortés for her assistance with molecular experiments; Isabel Aced López, a medical illustrator (https://www.issaced.com), for digitizing and enhancing the figures; and Darren Heath (CELTA ID: ccpf415440) for English language editing of the article. The authors also thank the anonymous reviewers for their constructive feedback, which helped to improve the clarity and scientific rigor of the manuscript.

Funding

This work was supported by the Spanish State Research Agency and European Union NextGenerationEU/PRTR through project PID2019-109405R and grant RYC2021-032602-I; the Andalusian Plan for Research, Development, and Innovation and ERDF/EU through project P20_00811 and fellowship PREDOC_02201; and the Instituto de Salud Carlos III (ISCIII) co-funded by the European Union, through project PI22/01379, the Sara Borrell fellowship (CD19_00183), the M-AES mobility grant (MV22/00107), and unrestricted research funding from the Spanish Network for Research in Mental Health (CIBERSAM, G26).

Author information

Authors and Affiliations

  1. Translational Psychiatry Group, Seville Biomedical Research Institute (IBiS)-CSIC, Seville, Spain

    Susana García-Cerro, Ana Gómez-Garrido & Benedicto Crespo-Facorro

  2. Mental Health Biomedical Research Network Center (CIBERSAM-ISCIII)-G26, Madrid, Spain

    Susana García-Cerro, Ana Gómez-Garrido & Benedicto Crespo-Facorro

  3. Achucarro Basque Center for Neuroscience, Leioa, Spain

    Federico N. Soria

  4. Ikerbasque, Basque Foundation for Science, Bilbao, Spain

    Federico N. Soria

  5. Andalusian Public Foundation Progress and Health (FPS), Seville, Spain

    Carlos Loucera

  6. Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Virgen del Rocio University Hospital, Seville, Spain

    Carlos Loucera

  7. Rare Diseases Biomedical Research Network Center (CIBERER-ISCIII)-U715, Seville, Spain

    Carlos Loucera

  8. Digital Department of Biomedical and Health Sciences, Faculty of Biomedical and Health Sciences, European University of Madrid, Villaviciosa de Odón, Spain

    Carlos Loucera

  9. Mental Health Unit, Virgen del Rocio University Hospital, Seville, Spain

    Benedicto Crespo-Facorro

  10. Department of Psychiatry, Faculty of Medicine, University of Seville, Seville, Spain

    Benedicto Crespo-Facorro

Authors
  1. Susana García-Cerro
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  2. Ana Gómez-Garrido
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  3. Federico N. Soria
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  4. Carlos Loucera
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  5. Benedicto Crespo-Facorro
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Contributions

SG-C conceived and designed the study, performed the experiments, analyzed the data, and wrote the manuscript. AG-G performed the experiments. FNS contributed to the analysis of PNN fine morphology. CL contributed to the MATLAB analysis. Funding was provided by BC-F, who also contributed to the conceptual framework, offered suggestions, and critically reviewed the manuscript. AG-G, FNS, CL, and BC-F reviewed and refined the final version of the manuscript. All authors have read and approved the published version of the manuscript.

Corresponding author

Correspondence to Susana García-Cerro.

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García-Cerro, S., Gómez-Garrido, A., Soria, F.N. et al. Clozapine induces perineuronal net remodeling in a developmental mouse model exhibiting schizophrenia-relevant phenotypes. Neuropsychopharmacol. (2025). https://doi.org/10.1038/s41386-025-02210-3

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  • DOI: https://doi.org/10.1038/s41386-025-02210-3

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