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Tic-related behaviors in Celsr3 mutant mice are contributed by alterations of striatal D3 dopamine receptors

Molecular Psychiatry volume 30, pages 3912–3924 (2025)Cite this article

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Abstract

The gene CELSR3 (Cadherin EGF LAG Seven‐pass-G‐type Receptor 3) has been recently recognized as a high-confidence risk factor for Tourette syndrome (TS). Additionally, Celsr3 mutant mice have been reported to exhibit TS-related behaviors and increased dopamine release in the striatum. Building on these findings, we further characterized the neurobehavioral and molecular profile of Celsr3 mutant mice to understand better the biological mechanisms connecting the deficiency of this gene and TS-related phenotypes. Our analyses confirmed that Celsr3 mutant mice displayed grooming stereotypies and tic-like jerks, as well as sensorimotor gating deficits, which were opposed by TS therapies. Spatial transcriptomic analyses revealed widespread extracellular matrix abnormalities in the striatum of Celsr3 mutants. Single-nucleus transcriptomics also showed significant upregulation of the Drd3 gene, encoding the dopamine D3 receptor, in striosomal D1-positive neurons. In situ hybridization and immunofluorescence confirmed dysregulated D3 receptor expression, with lower levels in presynaptic striatal fibers and higher levels in striatal D1-positive neurons. Activating and blocking D3 receptors amplified or decreased tic-like jerks and stereotypies in Celsr3-deficient mice, respectively. These findings suggest that modifications of D3 receptor distribution contribute to the tic-like responses associated with Celsr3 deficiency.

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Fig. 1: Adolescent and juvenile Celsr3 heterozygous (HZ) mice show spontaneous behavioral alterations related to Tourette syndrome (TS).
Fig. 2: Tourette syndrome therapies are effective against the spontaneous tic-like behaviors of Celsr3 heterozygous (HZ) mice.
Fig. 3: Spatial Transcriptomic Analyses of the Striatum in Celsr3 heterozygous (HZ) mice reveal inflammatory alterations and reductions in collagen-containing matrix.
Fig. 4: Single-nucleus transcriptomic analyses of neuron-associated clusters of Celsr3 heterozygous (HZ) and wild-type (WT) reveal alteration in microtubule organization and signaling in select neuronal clusters.
Fig. 5: Celsr3 heterozygous (HZ) mice exhibit alterations in striatal D3 dopamine receptors.
Fig. 6: D3 dopamine receptor activation worsens tic-like behaviors in Celsr3 heterozygous (HZ) mice, while antagonism reduces them.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The data generated for sn-RNA seq are available on Gene Expression Omnibus (GSE249902 and GSE280709).

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Acknowledgements

We acknowledge the Huntsman Cancer Institute High-throughput Genomics and Bioinformatics Center, as well as the HSC Cell Imaging Core, for enabling sh-RNA sequencing and IF microscopy analyses. We thank Karen Odeh, Job Huxford, Elise Vandamme, and Easton Van Luik for their technical assistance with animal testing. We thank Anton Classen for his invaluable support in image acquisition and analysis.

Funding

This study was partially supported by the NIH grant R21 NS125519 (to MB).

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA

    Roberto Cadeddu, Caterina Branca, Giulia Braccagni, Teresa Musci, Philip J. Moos & Marco Bortolato

  2. Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA

    Caterina Branca, Giulia Braccagni & Marco Bortolato

  3. Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA

    Ignazio S. Piras & Matthew J. Huentelman

  4. Department of Neurology, School of Medicine, University of Utah, Salt Lake City, UT, USA

    Collin J. Anderson

  5. School of Medical Sciences, University of Sydney, Camperdown, NSW, Australia

    Collin J. Anderson

  6. School of Biomedical Engineering, University of Sydney, Camperdown, NSW, Australia

    Collin J. Anderson

  7. Department of Human Genetics, College of Medicine, University of Utah, Salt Lake City, UT, USA

    Mario R. Capecchi

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  1. Roberto Cadeddu
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  2. Caterina Branca
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  10. Marco Bortolato
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Contributions

Conceptualization: MB; Methodology: RC, CB, GB, TM, IP, CA, MC, MH, and PM; Formal analysis: RC, CB, GB, TM, IP, CA, MC, MH, PM, and MB; Writing: MB produced the initial manuscript, and all others reviewed and commented on the manuscript; Supervision: MB; Funding Acquisition: MB.

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Correspondence to Marco Bortolato.

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All methods in this study were conducted in compliance with relevant guidelines and regulations. Animal procedures were carried out in accordance with these standards and were approved by the Institutional Animal Care and Use Committees (IACUC) at the respective institutions under protocol numbers 21-11004 (University of Utah) and IACUC202400000556 (University of Florida).

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Cadeddu, R., Branca, C., Braccagni, G. et al. Tic-related behaviors in Celsr3 mutant mice are contributed by alterations of striatal D3 dopamine receptors. Mol Psychiatry 30, 3912–3924 (2025). https://doi.org/10.1038/s41380-025-02970-w

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