DISTINCT PATTERNS OF CEREBELLAR DEGENERATION AND NEUROGLIAL ACTIVATION IN MOUSE MODELS OF ATAXIA

Aims: Our prior transplantation studies revealed strain-dependent behavior of identical neural stem cell grafts, prompting analysis of microglial and astrocytic activity as determinants of graft survival and migration.
Methods: Six-month-old B6.BR Purkinje cell degeneration (pcd) and B6CBA Lurcher mice with clinical signs of cerebellar degeneration, along with strain-matched healthy controls (n = 6 per group), were perfusion-fixed and processed for histological analysis. Sagittal cerebellar sections were immunofluorescently labeled for microglia (Iba1) and astrocytes (GFAP), while Nissl-stained sections were used for stereological estimation of cerebellar layer volumes. Fluorescence signal intensity was quantified from standardized images using ImageJ/Fiji. Statistical analysis employed permutation-based ANOVA with appropriate post hoc testing and correction for multiple comparisons.
Results: Both pcd and Lurcher mutant mice showed a marked reduction in total cerebellar volume compared with healthy controls, with degeneration being more severe in Lurcher mice. The most pronounced structural losses affected the molecular layer and Purkinje cell bodies, while changes in the granular layer closely followed this pattern. White matter volume decreased similarly in both models. In contrast, the volume of deep cerebellar nuclei decreased only in diseased Lurcher mice compared to healthy ones. Degeneration was accompanied by increased GFAP and Iba1 activity, showing region- and strain-specific patterns.
Conclusions: Cerebellar degeneration severity and glial responses differ between pcd and Lurcher mice, indicating that strain-specific tissue remodeling shapes distinct structural and inflammatory outcomes.
Supported by the Cooperatio Program (MED/DIAG and NEUR).