Output mapping of cerebellar nuclei in a mouse model of autism

The cerebellum plays a critical role in both motor and non-motor functions, and its dysfunction is linked to various mental disorders, including autism. This study maps the 3D distributions of 50,168 target neurons of cerebellar nuclei (CN) in wild-type and Nlgn3^R451C mutant mice. The researchers found that Nlgn3^R451C the mutation differentially affects projections from the CN to the thalamus, midbrain, and brainstem. Specifically, the mutation alters the innervation strength of the CN→zona incerta (ZI) pathway. Chemogenetic inhibition of a neuronal subpopulation in the ZI that receives inputs from the CN rescues social deficits in Nlgn3^R451C mice. These findings highlight the potential role of cerebellar outflows in the pathogenesis of autism and suggest new therapeutic strategies.

Key findings from the study include:

1. The Nlgn3^R451C The mutation differentially affects projections from the cerebellar nuclei (CN) to the thalamus, midbrain, and brainstem. The number of labeled neurons was decreased in the parabrachial nucleus (PB) and posterior thalamic nucleus (Po), increased in the zona incerta (ZI) and unchanged in other nuclei.
2. Subnuclear distribution analysis revealed that mutation-induced changes in neurons varied with the tachycardic nucleus (FN), mesopositive nucleus (IN), and dentate nucleus (DN). ZI consistently showed an increase in labeled neurons.
3. Chemogenetic inhibition of a specific neuronal subpopulation in the ZI, which receives inputs from the CN, rescued social deficits in Nlgn3^R451C mutant mice. This finding suggests a potential therapeutic target for autism.

This study provides a comprehensive understanding of structural and functional changes in the cerebellar output in a mouse model of autism. By mapping the projections and identifying specific changes in innervation patterns, the researchers highlight the importance of the cerebellum-thalamic-midbrain circuit in autism. Chemogenetic rescue of social deficits in Nlgn3^R451C mice offers a promising new therapeutic strategy for the treatment of autism spectrum disorders. The paper entitled “Aberrant outputs of cerebellar nuclei and targeted rescue of social deficits in autism mouse model” was published in Protein & Cell (published on July 27, 2024).