Study of Synaptic Function in Galactosyl-Ceramidase Deficient Mice

Synaptic failure is a major contributor to cognitive impairment in many neurological diseases. Krabbe disease (KD) is a lysosomal deficiency of galactosyl-ceramidase (GALC) that causes toxic accumulation of psychosine and global demyelination. KD patients develop major motor problems and become neurologically compromised. It is unknown whether synaptic function is also affected by the deficiency of GALC. Because psychosine is a lipid that disrupts the normal architecture of the membrane, altering associated signaling, we hypothesized that synaptic function is also impaired in KD. Using Golgi Cox staining, we found a significant decrease in the number of dendritic spines in cortical neurons of sick twitcher mice, the authentic murine model of infantile KD. Electron microscopy data confirmed ultrastructural alterations in many KD synapses in the cortex as well as in the hippocampus, with reduced contact area and lower number of synaptic vesicles. Levels of psychosine were elevated in synaptic membranes, in parallel with altered levels of several pre-synaptic SNARE proteins. Paired pulse facilitation was significantly reduced in hippocampal neurons of sick twitcher mice, as well as in additional mutants bearing other GALC mutations. Furthermore, conditional ablation of GALC in neurons but not in oligodendrocytes confirmed intrinsic deficits of synaptic transmission, independent from myelin defects. Together, these results support our hypothesis that KD synapses are structurally and functionally disrupted and provide a basis to understand neurological deficits observed in KD patients.