Mapping cerebellar nuclei outputs in an autistic mouse model

The cerebellum plays an essential role in 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 from wild-type and Nlgn3 cerebellar nuclei (CNs)^R451C mutant mice. The researchers discovered that Nlgn3^R451C the mutation differentially affects projections from the CN to the thalamus, midbrain, and brainstem. More precisely, the mutation modifies the innervation power of the CN → zona incerta (ZI) pathway. Chemogenetic inhibition of a neuronal subpopulation of the ZI that receives information from the CN rescues social deficits of Nlgn3^R451C mouse. These results highlight the potential role of cerebellar secretions in the pathogenesis of autism and suggest new therapeutic strategies.

The main findings of 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 decreased in the parabrachial nucleus (PB) and posterior thalamic nucleus (Po), increased in the zone incerta (ZI) and unchanged in the other nuclei.
2. Subnuclear distribution analysis revealed that mutation-induced changes in innervations varied depending on the fastigial nucleus (FN), interpositus nucleus (IN), and dentate nucleus (DN). ZI consistently showed an increase in the number of labeled neurons.
3. Chemogenetic inhibition of a specific neuronal subpopulation of the ZI, which receives information from the CN, rescued the social deficits of 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 of cerebellar outputs in an autistic mouse model. By mapping projections and identifying specific changes in innervation patterns, researchers highlight the importance of the cerebellar-thalamic-midbrain circuit in autism. Chemogenetic rescue of social deficits in Nlgn3^R451C Mice offer a promising new therapeutic strategy for treating autism spectrum disorders. The work, entitled “Aberrant cerebellar nuclei outputs and targeted rescue of social deficits in an autistic mouse model” was published on Proteins and cells (published July 27, 2024).