GDNF and IGF-I trophic factors delay hereditary Purkinje cell degeneration and the progression of gait ataxia.

Neurotrophic factors GDNF and/or IGF-I were chronically infused into shaker mutant rats to rescue cerebellar Purkinje neurons from adult-onset heredodegeneration. The natural expression of the shaker mutation is characterized by spatially restricted degeneration of Purkinje cells that occurs earlier and faster in an anterior vermal compartment and slightly later and more slowly in a posterior vermal compartment. Gait ataxia and whole body tremor develop concomitant with the degeneration of Purkinje neurons. The number and spatial distribution of surviving Purkinje neurons, identified by cell-specific calbindin immunoreactivity, were quantitatively analyzed in mid-sagittal sections and correlated with quantitative movement analysis of hindlimb gait patterns. Compared to the number of surviving Purkinje cells in age-matched, non-infused, or saline-infused control mutants, 4 weeks of infusion of GDNF or IGF-I rescued many anterior compartment Purkinje cells from early degeneration. However, 2 and 4 weeks after cessation of GDNF or IGF-I infusion, respectively, the number and spatial distribution of surviving Purkinje cells was comparable to that observed in age-matched controls. Eight weeks of infusion of trophic factors did not support the continued survival of most anterior compartment Purkinje cells and was partially, and probably only transiently, neuroprotective for some posterior compartment Purkinje cells. When GDNF and IGF-I were infused together for 4 weeks the number of surviving Purkinje cells was additively greater than with either factor alone. Behaviorally, 4 weeks of infusion of trophic factors delayed the development of gait ataxia. Infused GDNF appeared to preserve hip stability, whereas IGF-I stabilized step length. Tremor was attenuated with 8 weeks of infusion of GDNF or IGF-I. GDNF-infused animals showed low power tremor frequencies, whereas IGF-I infusion resulted in a single large power peak with decreased numbers of low-amplitude frequencies. Collectively these findings indicate that exogenous trophic factors can delay the onset of hereditary Purkinje cell degeneration and gait ataxia. Quite surprisingly, GDNF and IGF-I appeared to act on disparate populations of mutant Purkinje cells, whose differential survival affected different aspects of locomotion.