Cerebellar Nuclei Fix Eases Autism Symptoms in Mice

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 three-dimensional distributions of 50,168 target neurons of cerebellar nuclei (CN) in wild-type and Nlgn3^R451C mutant mice. The researchers found that the Nlgn3^R451C mutation differentially affects projections from CN to the thalamus, midbrain, and brainstem. Specifically, the mutation alters the innervation power 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 outputs in the pathogenesis of autism and suggest new therapeutic strategies.

Key findings from the study include:

1. The Nlgn3^R451C mutation differentially affects the projections from 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 the mutation-induced changes in innervations varied with the fastigial nucleus (FN), interpositus nucleus (IN), and dentate nucleus (DN). The 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 the structural and functional alterations in cerebellar outputs in an autism mouse model. By mapping the projections and identifying specific changes in innervation patterns, the researchers highlight the importance of the cerebellar-thalamic-midbrain circuit in autism. The chemogenetic rescue of social deficits in Nlgn3^R451C mice offers a promising new therapeutic strategy for treating autism spectrum disorders. The work entitled " Aberrant outputs of cerebellar nuclei and targeted rescue of social deficits in an autism mouse model " was published on Protein & Cell (published on Jul. 27, 2024).