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

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.

Characterizing cerebellar development in Chd8 haploinsufficient mice, Seban et al. identify transcriptomic perturbations across major cerebellar cell types, most prominently in Purkinje cells, accompanied by altered Purkinje cell morphology and function. These findings highlight the cerebellum as a key contributor to CHD8 -associated neurodevelopmental disorders.

Molecular profiling defines cerebellar pathology in Chd8 +/- mice Interneurons and granule cells exhibit precocious maturation at P12Purkinje cell transcriptomic burden aligns with morpho-electric defectsBulk RNA-seq reveals long-lasting cerebellar pathology into adulthood.