REGION-SPECIFIC SYNAPTIC ADAPTATIONS IN A MOUSE MODEL OF SPINOCEREBELLAR ATAXIA TYPE 6

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease characterized by progressive cerebellar dysfunction. In both patients and a knock-in mouse model of SCA6 (SCA6^84Q/84Q), cerebellar degeneration occurs in a region-specific manner: Purkinje cells in anterior lobules exhibit early dysfunction and later degeneration, whereas posterior regions remain relatively preserved. We combined transcriptomic, structural, and electrophysiological approaches to examine mechanisms underlying this differential vulnerability across regions in SCA6 cerebellum. Unexpectedly, RNA sequencing revealed many differentially expressed genes in the resilient posterior SCA6 cerebellum with changes especially in parallel fiber (PF)–Purkinje cell excitatory synapses. Consistent with this, we observed loss of PF synapses and reduced synaptic strength in the posterior SCA6 cerebellum. In contrast, the vulnerable anterior lobule III showed increased PF synaptic strength without detectable synapse loss, consistent with glutamate-mediated excitotoxicity. Together, these findings reveal divergent synaptic adaptations across cerebellar regions, suggesting that enhanced excitatory transmission may contribute to pathology in vulnerable circuits, while loss and weakening of synapses in preserved regions may represent a compensatory response that reduces glutamate excitotoxicity and cell death. Our findings demonstrate that brain regions spared from degeneration can nonetheless undergo dramatic alterations that may counteract but paradoxically also contribute to disease-related dysfunction.