Subtle gait abnormalities in Nedd4 heterozygous mice

Nedd4 is a widely expressed ubiquitin ligase that is necessary for normal neuronal development and function. However, largely due to the lethality of Nedd4 homozygous knockout mice, little is known about the physiological roles of Nedd4 in the adult brain. In this study we used Nedd4 heterozygous mice, which are viable and live to maturity, to assess for motor function and gait. Global motor function was not altered in these mice, a result consistent with the low level of Nedd4 expression observed in motor neurons of the spinal cord. However, Nedd4 heterozygous mice showed significant age-dependent changes in gait. The gait abnormalities included an overall extension of gait that was only evident in the 6 month old mice. We also observed distinct expression patterns of Nedd4, with pronounced staining in the Purkinje neurons of the cerebellum that are crucial for normal gait, and lower levels in other motor areas of the CNS. It has been recently shown that Nedd4 directly interacts with GluR1 containing AMPA receptors in an activity dependent manner to modulate receptor levels at the post-synaptic membrane. Using confocal immunohistochemistry, we found that there were subtle changes in GluR1 expression in 6 month old Nedd4 heterozygous mice. There appeared to be a redistribution of GluR1 into larger puncta in the molecular layer and in the membrane of the soma of the Purkinje neurons. This study is the first to show that a 50% reduction in Nedd4 levels is sufficient to produce significant gait defects in 6 month old mice. These defects may arise in part, from altered distribution of GluR1 in cerebellar neurons.