Tolbert Daniel L, Clark B Ruth
Department of Anatomy and Neurobiology, Saint Louis University School of Medicine, St Louis, MO 63104, USA.
Exp Neurol. 2003 Sep;183(1):205-19. doi: 10.1016/s0014-4886(03)00172-9.
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.
将神经营养因子胶质细胞源性神经营养因子（GDNF）和/或胰岛素样生长因子I（IGF-I）长期注入摇晃突变大鼠体内，以挽救成年期开始发生遗传性退变的小脑浦肯野神经元。摇晃突变的自然表现特征是浦肯野细胞在空间上受到限制的退变，这种退变在前蚓部隔室中发生得更早、更快，而在后蚓部隔室中稍晚且更慢。步态共济失调和全身震颤与浦肯野神经元的退变同时出现。通过细胞特异性钙结合蛋白免疫反应鉴定存活的浦肯野神经元的数量和空间分布，在矢状中切面上进行定量分析，并与后肢步态模式的定量运动分析相关联。与年龄匹配的未注入或注入生理盐水的对照突变体中存活的浦肯野细胞数量相比，注入GDNF或IGF-I 4周可挽救许多前隔室浦肯野细胞免于早期退变。然而，分别在停止注入GDNF或IGF-I 2周和4周后，存活的浦肯野细胞的数量和空间分布与年龄匹配的对照中观察到的情况相当。注入营养因子8周并不能支持大多数前隔室浦肯野细胞的持续存活，并且对一些后隔室浦肯野细胞具有部分（可能只是短暂的）神经保护作用。当GDNF和IGF-I一起注入4周时，存活的浦肯野细胞数量比单独使用任何一种因子时相加更多。在行为上，注入营养因子4周延迟了步态共济失调的发展。注入的GDNF似乎保持了髋关节稳定性，而IGF-I稳定了步长。注入GDNF或IGF-I 8周可减轻震颤。注入GDNF的动物表现出低功率震颤频率，而注入IGF-I导致单个大的功率峰值，低幅度频率数量减少。总体而言，这些发现表明外源性营养因子可延迟遗传性浦肯野细胞退变和步态共济失调的发作。非常令人惊讶的是，GDNF和IGF-I似乎作用于不同群体的突变浦肯野细胞，它们的差异存活影响了运动的不同方面。
