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.