The cerebellum is vital not only for motor learning and balance coordination but also involves language, emotional regulation, and neuropsychiatric disorders. Neuroligins are critical cell-adhesion molecules that bridge the synaptic gap between neurons in the cerebellum. They belong to a family of proteins (Nlgn1-Nlgn4) that interact with presynaptic neurexins, playing varied roles in synaptic transmission. Extensive research has demonstrated that while neuroligins are indispensable for shaping the properties of synapses, they do not initiate their formation. In the cerebellum, the deletion of specific neuroligins like Nlgn1 and Nlgn3 affects synaptic transmission through climbing fibres.

Recent studies have expanded our understanding of neuroligins beyond their neuronal functions, exploring their roles in astrocytes, a type of glial cell in the brain that has been traditionally underestimated in its contribution to synaptic connectivity and neuropsychiatric disorders. The cerebellum hosts various astrocytes, including Bergmann glia, which are intimately involved in maintaining synaptic function through mechanisms like glutamate clearance.

A collaborative study done by researchers from BGI-Research, Peking University Shenzhen Graduate School, and Stanford University, was recently published in Molecular Psychiatry. This study has shed light on the function of Neuroligin-3 (Nlgn3) in astrocytes, particularly in Bergmann glia of the cerebellum. Utilizing advanced techniques such as genomic editing and BGI’s spatial transcriptomic sequencing, Stereo-seq, researchers have discovered that Nlgn3 is predominantly located in the cell body of cerebellar astrocytes. This localization is distinct from its placement in neurons, where it typically resides at the synaptic junction and influences the clustering of postsynaptic AMPA receptors.

The study “Astrocytic Neuroligin-3 influences gene expression and social behavior, but is dispensable for synapse number” was published in Molecular Psychiatry.

The deletion of Nlgn3 in astrocytes revealed surprising findings. Contrary to its critical role at neuronal synapses, its absence in astrocytes does not affect the number or function of these synapses directly. Instead, Nlgn3 in astrocytes influences gene expression patterns across various cell types within the brain. This alteration in gene expression notably affects calcium homeostasis pathways, which are crucial for cell signalling and neural activity.

Behavioural studies on mice with astrocytic Nlgn3 deletion provided additional insights. These mice displayed increased novelty in their social interactions, suggesting that astrocytic Nlgn3 could modulate social behaviours - a finding that is particularly relevant given the known links between synaptic dysfunction and autism spectrum disorders. However, these changes occurred without any noticeable impact on motor skills or anxiety levels, indicating that the behavioural effects of Nlgn3 deletion are specific to social interaction pathways.

Ethical review approval was obtained for this study.

The study can be accessed here: https://www.nature.com/articles/s41380-024-02659-6