Zaman Vandana, Boger Heather A, Granholm Ann-Charlotte, Rohrer Baerbel, Moore Alfred, Buhusi Mona, Gerhardt Greg A, Hoffer Barry J, Middaugh Lawrence D
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
Eur J Neurosci. 2008 Oct;28(8):1557-68. doi: 10.1111/j.1460-9568.2008.06456.x.
Given the established importance of glial cell line-derived neurotrophic factor (GDNF) in maintaining dopaminergic neurotransmitter systems, the nigrostriatal system and associated behaviors of mice with genetic reduction of its high-affinity receptor, GDNF receptor (GFR)alpha-1 (GFRalpha-1(+/-)), were compared with wild-type controls. Motor activity and the stimulatory effects of a dopamine (DA) D1 receptor agonist (SKF 82958) were assessed longitudinally at 8 and 18 months of age. Monoamine concentrations and dopaminergic nerve terminals in the striatum and the number of dopaminergic neurons in the substantia nigra (SN) were assessed. The results support the importance of GFRalpha-1 in maintaining normal function of the nigrostriatal dopaminergic system, with deficits being observed for GFRalpha-1(+/-) mice at both ages. Motor activity was lower and the stimulatory effects of the DA agonist were enhanced for the older GFRalpha-1(+/-) mice. DA in the striatum was reduced in the GFRalpha-1(+/-) mice at both ages, and tyrosine hydroxylase-positive cell numbers in the SN were reduced most substantially in the older GFRalpha-1(+/-) mice. The combined behavioral, pharmacological probe, neurochemical and morphological measures provide evidence of abnormalities in GFRalpha-1(+/-) mice that are indicative of an exacerbated aging-related decline in dopaminergic system function. The noted deficiencies, in turn, suggest that GFRalpha-1 is necessary for GDNF to maintain normal function of the nigrostriatal dopaminergic system. Although the precise mechanism(s) for the aging-related changes in the dopaminergic system remain to be established, the present study clearly establishes that genetic reductions in GFRalpha-1 can contribute to the degenerative changes observed in this system during the aging process.
鉴于胶质细胞源性神经营养因子（GDNF）在维持多巴胺能神经递质系统方面已确立的重要性，将其高亲和力受体GDNF受体（GFR）α-1基因减少的小鼠（GFRα-1(+/-)）的黑质纹状体系统及相关行为与野生型对照进行了比较。在8个月和18个月龄时纵向评估运动活性以及多巴胺（DA）D1受体激动剂（SKF 82958）的刺激作用。评估纹状体中的单胺浓度、多巴胺能神经末梢以及黑质（SN）中多巴胺能神经元的数量。结果支持GFRα-1在维持黑质纹状体多巴胺能系统正常功能中的重要性，两个年龄的GFRα-1(+/-)小鼠均出现缺陷。对于年龄较大的GFRα-1(+/-)小鼠，运动活性较低，DA激动剂的刺激作用增强。两个年龄的GFRα-1(+/-)小鼠纹状体中的DA均减少，年龄较大的GFRα-1(+/-)小鼠SN中酪氨酸羟化酶阳性细胞数量减少最为显著。综合行为、药理学探针、神经化学和形态学测量结果提供了GFRα-1(+/-)小鼠异常的证据，表明多巴胺能系统功能与衰老相关的衰退加剧。这些明显的缺陷反过来表明，GFRα-1是GDNF维持黑质纹状体多巴胺能系统正常功能所必需的。尽管多巴胺能系统与衰老相关变化的确切机制仍有待确定，但本研究清楚地表明，GFRα-1的基因减少可导致该系统在衰老过程中出现退行性变化。
