Precocious maturation and Purkinje cell dysfunction in the mouse Chd8 haploinsufficient cerebellum

Abstract

The cerebellum plays an emerging, but understudied, role in neurodevelopmental disorders (NDDs). Mutations in CHD8 cause a monogenic NDD (CHD8-NDD) characterized by autism and other manifestations, and prior work in Chd8 mutant mice reported cerebellar abnormalities, raising the possibility of cerebellar contribution to CHD8-NDD. To comprehensively characterize the impact of Chd8 haploinsufficiency on cerebellar development and function, we profiled the postnatal day 12 (P12) cerebellum of germline Chd8+/- mice using transcriptomic, morphological, and electrophysiological approaches. Gross cerebellar morphology was unaffected, but single-nucleus RNA sequencing revealed transcriptomic signatures of pathophysiology across cell types, including accelerated maturation of molecular layer interneurons and granule cells, and altered myelination state of oligodendrocytes. Purkinje cells (PCs) showed the strongest transcriptomic burden of any cell type and, consistent with this, exhibited altered morphology and electrophysiological properties. Bulk RNA sequencing confirmed that transcriptomic pathology persists into adulthood, indicating lasting impacts on both neuronal and glial gene expression. Together, these results capture cell-type-specific cerebellar perturbations associated with Chd8 haploinsufficiency and support the cerebellum as a relevant site of pathology in CHD8-NDD.

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BibTeX

@misc{seban2026precocious,
  title = {{Precocious maturation and Purkinje cell dysfunction in the mouse Chd8 haploinsufficient cerebellum}},
  author = {N. Seban and E. Merino and A. D'Ambra and S. J. Jung and J. L. Dunga and S. Lozano and E. Fenton and N. Chu and K. Jackson and D. Rahbarian and A. Kopley-Smith and M. Corea and K. Cichewicz and C. Ardekani and E. G. Antzoulatos and C. P. Canales and D. Fioravante and A. S. Nord},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.26.754669},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.26.754669v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Precocious maturation and Purkinje cell dysfunction in the mouse Chd8 haploinsufficient cerebellum
AU  - N. Seban
AU  - E. Merino
AU  - A. D'Ambra
AU  - S. J. Jung
AU  - J. L. Dunga
AU  - S. Lozano
AU  - E. Fenton
AU  - N. Chu
AU  - K. Jackson
AU  - D. Rahbarian
AU  - A. Kopley-Smith
AU  - M. Corea
AU  - K. Cichewicz
AU  - C. Ardekani
AU  - E. G. Antzoulatos
AU  - C. P. Canales
AU  - D. Fioravante
AU  - A. S. Nord
PY  - 2026
DA  - 2026/09/26
PB  - bioRxiv
DO  - 10.64898/2026.09.26.754669
UR  - https://www.biorxiv.org/content/10.64898/2026.09.26.754669v1
AB  - The cerebellum plays an emerging, but understudied, role in neurodevelopmental disorders (NDDs). Mutations in CHD8 cause a monogenic NDD (CHD8-NDD) characterized by autism and other manifestations, and prior work in Chd8 mutant mice reported cerebellar abnormalities, raising the possibility of cerebellar contribution to CHD8-NDD. To comprehensively characterize the impact of Chd8 haploinsufficiency on cerebellar development and function, we profiled the postnatal day 12 (P12) cerebellum of germline Chd8+/- mice using transcriptomic, morphological, and electrophysiological approaches. Gross cerebellar morphology was unaffected, but single-nucleus RNA sequencing revealed transcriptomic signatures of pathophysiology across cell types, including accelerated maturation of molecular layer interneurons and granule cells, and altered myelination state of oligodendrocytes. Purkinje cells (PCs) showed the strongest transcriptomic burden of any cell type and, consistent with this, exhibited altered morphology and electrophysiological properties. Bulk RNA sequencing confirmed that transcriptomic pathology persists into adulthood, indicating lasting impacts on both neuronal and glial gene expression. Together, these results capture cell-type-specific cerebellar perturbations associated with Chd8 haploinsufficiency and support the cerebellum as a relevant site of pathology in CHD8-NDD.
ER  -

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