Aberrant Neural Outputs and Disrupted Neural Oscillations of the Cerebellar Nuclei in a Mouse Model of Fragile X Syndrome.

The cerebellum is heavily connected to other brain regions, playing a role in both motor and non-motor functions. Genetic mutations leading to cerebellar dysfunction are associated with autism spectrum disorder (ASD); however, cerebellar output has not yet been systematically studied in this context. Here, using Fmr1-knockout mice, a model for Fragile X syndrome, we mapped the three-dimensional distributions of target neurons in the deep cerebellar nuclei (DCN). We found that projections from the DCN to various forebrain nuclei were differentially and specifically altered in Fmr1-knockout mice. Furthermore, in vivo electrophysiology revealed disrupted neuronal firing patterns, loss of specific neuronal subtypes, and aberrant local field potential oscillations within the DCN of Fmr1-knockout mice, all in the absence of any morphological changes. Notably, these oscillations exhibited weakened θ, α, and β powers, while the γ power remained unchanged. Our study further demonstrated the nucleus-specific dysregulation of cerebellar outputs and associated network dysfunction in an ASD model, highlighting the cerebellum as a key node in the pathophysiology of different neurodevelopmental disorders.