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bioRxiv · 10.1101/2024.05.23.595498

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

Molitor, J.·Graniou, J.·Salin, P.·Castets, F.·Fatmi, A.·Kerkerian-Le Goff, L.·Fasano, L.·Caubit, X.·Gubellini, P.
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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 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 onto the pathogenesis of ASD-related stereotyped behaviors by pointing to abnormal developmental compartmentalization and activity of SCINs as a substrate.

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Molitor, J., Graniou, J., Salin, P., Castets, F., Fatmi, A., Kerkerian-Le Goff, L., Fasano, L., Caubit, X., Gubellini, P.. 2024-05-23. Altered striosome-matrix distribution and activity of striatal cholinergic interneurons in a model of autism-linked repetitive behaviors. https://doi.org/10.1101/2024.05.23.595498

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