DECODING AUTISM: THE ROLE OF CEREBELLAR CONNECTIONS AND GENETIC MUTATIONS IN SOCIAL BEHAVIOR

Introduction: Over the past few decades, the relevance of the cerebellar connectome is emerging. The cerebellum is heavily connected with other brain regions, including the thalamus and the cerebral cortex, sub-serving motor and non-motor functions. For example, cerebellar nuclei (CN) neurons can actively participate in decision-making and regulating reward, saliency, and satiation. Genetic mutations affecting neurons in the cerebellar cortex can result in mental diseases, such as autism. Given that many mutations leading to autism affect the development of the cerebellum from early on, it has been hypothesized that the connectivity of CN neurons with the cerebral cortex and subcortical systems may be affected in autism. This possibility aligns with the finding that dysfunctional projections from the cerebellum to the prefrontal cortex may contribute to social deficits in tuberous sclerosis. This study, authored by Xin-Yu Cai et al., delves into the cerebellar outputs in autism.

Key Findings on Genetic Mutations and Cerebellar Dysfunction: The study presents three-dimensional distributions of 50,168 target neurons of CN from wild-type mice and Nlgn3R451C mutant mice. The projections from CN to the thalamus, midbrain, and brainstem are differentially affected by the Nlgn3R451C mutation. Notably, the Nlgn3R451C mutation altered the innervation power of the CN→zona incerta (ZI) pathway. Furthermore, chemogenetic inhibition of a neuronal subpopulation in the ZI that receives inputs from the CN rescues social defects in Nlgn3R451C mice. These findings underscore the potential role of cerebellar outputs in the pathogenesis of autism and suggest new therapeutic strategies.

Innovative Tools Used in the Study: The research utilized a whole-brain transsynaptic tracing technique to analyze 36 thalamic, midbrain, and brainstem nuclei innervated by CN outputs. The study employed AAV1-hSyn-Cre-EGFP virus and Ai9 reporter mice, which express red tdTomato fluorescence in the presence of Cre, to identify CN-output receiving neurons. These innovative tools enabled the precise mapping and analysis of neuronal connections affected by the Nlgn3R451C mutation.

Differential Synaptic Connectivity: The study reveals that the Nlgn3R451C mutation distinctly alters the synaptic connections between the CN and various brain nuclei. Inhibition of ZIIN and ZIDN neurons rescues social defects in Nlgn3R451C mice. The research indicates that structural connectivity of the cerebellum with other brain regions is affected in autism, which partly explains its symptoms. There is a differential impact of the Nlgn3R451C mutation on FN, IN, and DN projections in 36 thalamic, midbrain, and brainstem nuclei. These differential synaptic connections provide insights into how genetic mutations can lead to autistic-like behaviors.

Conclusion: In summary, the Nlgn3R451C mutation changes cerebellar outputs, differentially altering synaptic connections in various brain nuclei. The study underscores the potential role of cerebellar outputs in the pathogenesis of autism and suggests new therapeutic strategies. Understanding these structural changes in brain circuits provides valuable insights into how genetic mutations can lead to autistic-like behaviors, highlighting the importance of further research in this area.

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Original Research - The original research, titled "Aberrant outputs of cerebellar nuclei and targeted rescue of social deficits in an autism mouse model," can be found on PubMed here.