Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, CIBERER Unit 761, ISCiii, IdiPAZ, Arturo Duperier 4, 28029 Madrid, Spain.
Neurobiol Dis. 2012 May;46(2):476-85. doi: 10.1016/j.nbd.2012.02.013. Epub 2012 Feb 28.
Mutations in the gene encoding human insulin-like growth factor-I (IGF-I) cause syndromic neurosensorial deafness. To understand the precise role of IGF-I in retinal physiology, we have studied the morphology and electrophysiology of the retina of the Igf1(-/-) mice in comparison with that of the Igf1(+/-) and Igf1(+/+) animals during aging.
Serological concentrations of IGF-I, glycemia and body weight were determined in Igf1(+/+), Igf1(+/-) and Igf1(-/-) mice at different times up to 360days of age. We have analyzed hearing by recording the auditory brainstem responses (ABR), the retinal function by electroretinographic (ERG) responses and the retinal morphology by immunohistochemical labeling on retinal preparations at different ages.
IGF-I levels are gradually reduced with aging in the mouse. Deaf Igf1(-/-) mice had an almost flat scotopic ERG response and a photopic ERG response of very small amplitude at postnatal age 360days (P360). At the same age, Igf1(+/-) mice still showed both scotopic and photopic ERG responses, but a significant decrease in the ERG wave amplitudes was observed when compared with those of Igf1(+/+) mice. Immunohistochemical analysis showed that P360 Igf1(-/-) mice suffered important structural modifications in the first synapse of the retinal pathway, that affected mainly the postsynaptic processes from horizontal and bipolar cells. A decrease in bassoon and synaptophysin staining in both rod and cone synaptic terminals suggested a reduced photoreceptor output to the inner retina. Retinal morphology of the P360 Igf1(+/-) mice showed only small alterations in the horizontal and bipolar cell processes, when compared with Igf1(+/+) mice of matched age.
In the mouse, IGF-I deficit causes an age-related visual loss, besides a congenital deafness. The present results support the use of the Igf1(-/-) mouse as a new model for the study of human syndromic deaf-blindness.
人类胰岛素样生长因子-I（IGF-I）基因的突变会导致综合征性感觉神经性耳聋。为了了解 IGF-I 在视网膜生理学中的精确作用，我们研究了 Igf1(-/-) 小鼠的视网膜形态和电生理学，将其与 Igf1(+/-)和 Igf1(+/+)动物进行了比较，研究对象包括衰老过程中的动物。
在不同时间点，通过血清 IGF-I 浓度、血糖和体重测定，研究了 Igf1(+/+)、Igf1(+/-)和 Igf1(-/-) 小鼠，研究时间长达 360 天。我们通过记录听觉脑干反应（ABR）分析听力，通过视网膜电图（ERG）反应分析视网膜功能，通过免疫组织化学标记分析视网膜形态，在不同年龄的视网膜切片上进行了分析。
IGF-I 水平在小鼠衰老过程中逐渐降低。耳聋 Igf1(-/-) 小鼠在出生后 360 天（P360）时，具有几乎平坦的暗视 ERG 反应和非常小幅度的光视 ERG 反应。在同一年龄，Igf1(+/-) 小鼠仍显示出暗视和光视 ERG 反应，但与 Igf1(+/+) 小鼠相比，ERG 波幅度显著降低。免疫组织化学分析表明，P360 Igf1(-/-) 小鼠在视网膜通路的第一个突触中遭受了重要的结构改变，这主要影响了水平细胞和双极细胞的突触后过程。棒状和突触小泡蛋白染色在视杆和视锥突触末梢的减少表明，光感受器向视网膜内层的输出减少。与年龄匹配的 Igf1(+/+) 小鼠相比，P360 Igf1(+/-) 小鼠的水平细胞和双极细胞过程只有较小的改变。
在小鼠中，IGF-I 缺乏会导致与年龄相关的视力丧失，此外还会导致先天性耳聋。本研究结果支持使用 Igf1(-/-) 小鼠作为研究人类综合征性耳聋-失明的新模型。
