Early Neuroimmune Modulation in Hereditary Cerebellar Ataxias: Experimental Opportunities in Zebrafish Models

Hereditary cerebellar ataxias are progressive neurodegenerative disorders for which disease-modifying treatments remain lacking. Although these conditions have traditionally been investigated from a neuron-centered perspective, evidence from several ataxia models indicates that changes in the cerebellar immune microenvironment can arise before overt neuronal loss and may contribute to early circuit dysfunction. This review examines hereditary cerebellar ataxias through the lens of early neuroimmune regulation, with particular attention to the region-specific properties of cerebellar microglia and their roles in synaptic refinement, inflammatory tone modulation and circuit homeostasis. We further discuss zebrafish as a useful experimental system for this question, because they combine in vivo imaging, genetic manipulation, and scalable functional assays in an intact vertebrate model. In this context, flavonoids-and especially naringenin-are not considered as immediate therapeutic candidates, but as mechanistically informative experimental probes to investigate how modulation of neuroimmune signaling affects disease-relevant phenotypes in vivo. By integrating genetic ataxia models with dynamic neuroimmune readouts, functional behavioral assays, and circuit-level analyses, zebrafish-based approaches can help identify early windows during which neuroimmune signaling influences cerebellar resilience and disease progression and can guide subsequent validation in mammalian systems.