Blum M, Weickert C, Carrasco E
Fishberg Research Center for Neurobiology, Mt. Sinai School of Medicine, New York, New York 10029, USA.
Exp Neurol. 1999 Dec;160(2):413-24. doi: 10.1006/exnr.1999.7231.
The selective neurodegenerative changes occurring in the weaver mutant cerebellum and midbrain are linked to a point mutation in an inward rectifying potassium channel (GIRK2). However, given that GIRK2 is widely expressed in the CNS, it is not understood why this mutation only leads to neuroanatomically selective and developmentally specific neuronal cell death. Here we show that the phenotype of the weaver mutant mouse includes hypothyroidism, which is associated with delays in somatic development and decreased expression of striatal transforming growth factor alpha (TGF-alpha). Since thyroid hormone has major effects on brain development, further studies were performed to address whether some of pathological changes detected the weaver mutant mouse are due to the reduced thyroid hormone levels. We observed that daily thyroid hormone replacement was able to stimulate somatic growth and restore TGF-alpha expression to wild-type levels, indicating that while these mice are responsive to thyroid hormone they possibly have a defect in the ability to regulate its release at the level of the hypothalamic pituitary axis. However, when we assessed whether thyroid hormone replacement could rescue midbrain dopaminergic neurons we found that this treatment accelerated rather than attenuated neurodegeneration. We did not observe that thyroid hormone was able to directly regulate expression of GIRK2 mRNA levels in the midbrain and therefore, speculate that the mechanism by which thyroid hormone accelerates midbrain dopaminergic neurodegeneration is by enhancing the maturation of the striatonigral inputs. In summary, we detected reduced levels of serum thyroid hormone in the weaver mutant mouse, which appears to be responsible for delays in somatic growth and the onset of neurodegenerative changes in the midbrain.
在韦弗突变型小鼠的小脑和中脑中发生的选择性神经退行性变化与内向整流钾通道（GIRK2）中的一个点突变有关。然而，鉴于GIRK2在中枢神经系统中广泛表达，目前尚不清楚为什么这种突变仅导致神经解剖学上选择性的和发育特异性的神经元细胞死亡。在这里，我们表明韦弗突变型小鼠的表型包括甲状腺功能减退，这与躯体发育延迟和纹状体转化生长因子α（TGF-α）表达降低有关。由于甲状腺激素对脑发育有重大影响，因此进行了进一步研究，以探讨在韦弗突变型小鼠中检测到的一些病理变化是否是由于甲状腺激素水平降低所致。我们观察到，每日补充甲状腺激素能够刺激躯体生长，并将TGF-α表达恢复到野生型水平，这表明虽然这些小鼠对甲状腺激素有反应，但它们可能在调节下丘脑-垂体轴水平上甲状腺激素释放的能力方面存在缺陷。然而，当我们评估补充甲状腺激素是否能挽救中脑多巴胺能神经元时，我们发现这种治疗加速而非减轻了神经退行性变。我们没有观察到甲状腺激素能够直接调节中脑中GIRK2 mRNA水平的表达，因此推测甲状腺激素加速中脑多巴胺能神经退行性变的机制是通过增强纹状体黑质输入的成熟。总之，我们在韦弗突变型小鼠中检测到血清甲状腺激素水平降低，这似乎是导致躯体生长延迟和中脑神经退行性变发生的原因。
