Tolbert D L, Clark B R
Francis and Doris Murphy Neuroanatomy Research Laboratory, Department of Anatomy and Neurobiology, and Department of Surgery (Neurosurgery), Saint Louis University School of Medicine, St Louis, MO 63104, USA.
Neuroscience. 2000;101(2):417-33. doi: 10.1016/s0306-4522(00)00362-6.
Brainstem inferior olivary neurons, through their olivocerebellar efferent projections, dynamically regulate the structure and function of Purkinje neurons. To test the hypothesis that the inferior olive can epigenetically modify adult-onset hereditary Purkinje cell death, olivocerebellar projections were destroyed by 3-acetylpyridine chemoablation of the inferior olive in Shaker mutant rats. Starting around seven weeks of age, mutant Purkinje cells degenerate in a highly predictable spatial and temporal pattern. Chemoablation of the inferior olive at the onset of hereditary Purkinje cell degeneration accelerated the temporal pattern of Purkinje cell death from a natural phenotypic course of six to eight weeks to one and two weeks. When chemoablation of the inferior olive was performed three and a half weeks earlier, the onset of Purkinje cell death was accelerated by seven to 10days, but the spatial pattern and natural rate of temporal degeneration was maintained. Chemoablation of the inferior olive in normal rats did not result in any apparent death of Purkinje cells. These findings indicate that the olivocerebellar system can markedly modify hereditary Purkinje cell death. The accelerated death of Purkinje cells following chemoablation of the inferior olive can result from either the interruption of a trophic signal by climbing fiber deafferentation or parallel fiber excitotoxicity due to cortical disinhibition, but not due to olivocerebellar excitotoxicity.
脑干下橄榄核神经元通过其橄榄小脑传出投射，动态调节浦肯野神经元的结构和功能。为了验证下橄榄核可以通过表观遗传修饰成年期遗传性浦肯野细胞死亡这一假说，在摇椅突变大鼠中，通过3-乙酰吡啶化学消融下橄榄核来破坏橄榄小脑投射。从大约7周龄开始，突变型浦肯野细胞以高度可预测的空间和时间模式发生退化。在遗传性浦肯野细胞退化开始时进行下橄榄核化学消融，将浦肯野细胞死亡的时间模式从自然表型过程的6至8周加速至1至2周。当下橄榄核化学消融提前3.5周进行时，浦肯野细胞死亡的起始时间提前了7至10天，但空间模式和自然时间退化速率得以维持。正常大鼠下橄榄核化学消融未导致浦肯野细胞出现任何明显死亡。这些发现表明，橄榄小脑系统可显著改变遗传性浦肯野细胞死亡。下橄榄核化学消融后浦肯野细胞加速死亡可能是由于攀缘纤维脱失传入导致营养信号中断，或者是由于皮质去抑制引起的平行纤维兴奋性毒性，但不是由于橄榄小脑兴奋性毒性。
