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Altered striosome-matrix distribution and activity of striatal cholinergic interneurons in a model of autism-linked repetitive behaviors

Molecular Psychiatry (2025)Cite this article

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Abstract

Repetitive behaviors are cardinal features of many brain disorders, including autism spectrum disorder (ASD). We previously associated dysfunction of striatal cholinergic interneurons (SCINs) with repetitive behaviors in a mouse model based on conditional deletion of the ASD-related gene Tshz3 in cholinergic neurons (Chat-cKO). Here, we provide evidence linking SCIN abnormalities to the unique organization of the striatum into striosome and matrix compartments, whose imbalances are implicated in several pathological conditions. Chat-cKO mice exhibit an altered relationship between the embryonic birthdate of SCINs and their adult striosome-matrix distribution, leading to an increased proportion of striosomal SCINs. In addition, the ratio of striosomal SCINs with slow-irregular vs. sustained-regular firing is increased, which translates into decreased activity, further stressing the striosome-matrix imbalance. These findings provide novel insights into the pathogenesis of ASD-related stereotyped behaviors by pointing to abnormal developmental compartmentalization and activity of SCINs as a substrate.

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Fig. 1: Expression of cholinergic markers and Tshz3 in the embryonic mouse brain and Tshz3 deletion in Chat-cKO mice.
Fig. 2: Altered relationship between the birthdates of SCINs and their compartmental distribution in Chat-cKO mice.
Fig. 3: Unchanged numbers of SCINs in the dorsal striatum and its mediolateral subdivisions in Chat-cKO mice.
Fig. 4: No change in the area of the striatum and of the striosomal compartment in Chat-cKO mice.
Fig. 5: Enrichment of SCINs, but not of SSPNs, in the striosome compartment of Chat-cKO mice.
Fig. 6: Changes in the firing features of SCINs in Chat-cKO mice.
Fig. 7: Enrichment of SCINs with low frequency/irregular firing in the striosomes of Chat-cKO mice.
Fig. 8: Reduced VAChT expression in Chat-cKO mice.

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Raw data sets will be made available upon reasonable request to the corresponding authors.

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Acknowledgements

We wish to thank the imaging facility at the IBDM, member of the National Infrastructure France-BioImaging (https://ror.org/01y7vt929) supported by the French National Research Agency (ANR-24-INBS-0005 FBI BIOGEN), and the IBDM mouse facility.

Funding

This work received support from the French government under the Programme “Investissements d’Avenir”, Initiative d’Excellence d’Aix-Marseille Université via A*Midex funding (NeuroMarseille Institute, AMX-19-IET-004; MarMaRa Institute, AMX-19-IET-007), the French National Research Agency (ANR) “TSHZ3inASD” project grant n°ANR-17-CE16-0030-01 (to LF and LK-LG), the Fédération pour la Recherche sur le Cerveau (to LF), the Centre National de la Recherche Scientifique (CNRS), and Aix-Marseille University. JM and JG were supported by PhD grants from the Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation.

Author information

Author notes

  1. These authors contributed equally: Jordan Molitor, Juliette Graniou, Pascal Salin.

Authors and Affiliations

  1. Aix-Marseille Univ, CNRS, IBDM, UMR7288, Marseille, France

    Jordan Molitor, Juliette Graniou, Pascal Salin, Francis Castets, Ahmed Fatmi, Lydia Kerkerian-Le Goff, Laurent Fasano & Xavier Caubit

  2. Aix-Marseille Univ, CNRS, CRPN, UMR7077, Marseille, France

    Juliette Graniou & Paolo Gubellini

Authors
  1. Jordan Molitor
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  2. Juliette Graniou
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  3. Pascal Salin
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  4. Francis Castets
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  5. Ahmed Fatmi
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  6. Lydia Kerkerian-Le Goff
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  7. Laurent Fasano
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  8. Xavier Caubit
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  9. Paolo Gubellini
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Contributions

JM, JG, PS and XC performed the histological experiments and the quantitative analyses. JM and PG performed the patch-clamp experiments and analyzed the electrophysiological data. JM, JG and XC generated and maintained the transgenic mouse lines. FC performed western blot experiments. AF performed the qRT-PCR experiments and analyzed the data. JM, JG, XC and AF performed mouse genotyping. LK-LG, LF, XC and PG conceived the project, supervised the work and wrote the paper. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Laurent Fasano, Xavier Caubit or Paolo Gubellini.

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The authors declare no competing interests.

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Molitor, J., Graniou, J., Salin, P. et al. Altered striosome-matrix distribution and activity of striatal cholinergic interneurons in a model of autism-linked repetitive behaviors. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03208-5

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  • DOI: https://doi.org/10.1038/s41380-025-03208-5

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