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An ace in the hole? Opportunities and limits of using mice to understand schizophrenia neurobiology

Molecular Psychiatry volume 30, pages 4384–4398 (2025)Cite this article

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Abstract

In applying model organisms to study the neurobiology of mental disorders, rodents offer unique potential for probing, with high spatiotemporal resolution, the neural and molecular mechanisms underlying behavior in a mammalian system. Furthermore, investigators can wield exceptional power to manipulate genes, molecules, and circuits in mice to pin down causal relationships. While these advantages have allowed us to understand much more deeply than ever before the brain mechanisms regulating complex behaviors, the impact of rodent models on developing therapeutic strategies for psychiatric disorders has remained thus far limited. Herein, we will discuss the opportunities and limits of using mouse models in the context of schizophrenia, a complex psychiatric disorder with strong genetic basis that poses various unmet clinical needs calling out for basic science research. We review approaches for employing behavioral, genetic, and circuit-based methods in rodents to inform schizophrenia symptomatology, pathophysiology, and, ultimately, treatment.

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Fig. 1: Comparison of four rodent behavioral paradigms used to model positive symptoms of schizophrenia—pre-pulse inhibition (PPI) of startle, mismatch negativity (MMN), corollary discharge (CD), and signal detection task (SDT).
Fig. 2: Summary of 22q11.2 microdeletion mouse model phenotypes with demonstrated rescue methods.
Fig. 3: Schematic overview of rodent brain circuits with relevance for schizophrenia neurobiology.

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Acknowledgements

We would like to thank Ragy Girgis, Sarah Canetta, and Mark Ansorge for providing valuable feedback to the manuscript. Figures were created using assets from BioRender. This work was supported by the National Institute of Health (R01 MH136672, R01 MH128293 and R01 MH124858 to C.K. and K08 MH138822 to J.M.V).

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  1. Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, 10032, USA

    Joseph M. Villarin & Christoph Kellendonk

  2. Department of Psychiatry, Columbia University, New York, NY, 10032, USA

    Joseph M. Villarin & Christoph Kellendonk

  3. Department of Molecular Pharmacology & Therapeutics, Columbia University, New York, NY, 10032, USA

    Christoph Kellendonk

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Villarin, J.M., Kellendonk, C. An ace in the hole? Opportunities and limits of using mice to understand schizophrenia neurobiology. Mol Psychiatry 30, 4384–4398 (2025). https://doi.org/10.1038/s41380-025-03060-7

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