Schirmer Marko, Kaiser Alexander, Lessenich Alina, Lindemann Sven, Fedrowitz Maren, Gernert Manuela, Löscher Wolfgang
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Bünteweg 17, Hannover, Germany.
Brain Res. 2007 Jun 25;1155:179-95. doi: 10.1016/j.brainres.2007.04.012. Epub 2007 Apr 11.
The clinical usefulness of aminoglycoside antibiotics is limited by their ototoxicity. In rodents, damage to the inner ear is often associated with rotational behavior and locomotor hyperactivity reminiscent of such behaviors resulting from an imbalance of forebrain dopamine systems. Based on previous observations in the circling (ci2/ci2) Lewis (LEW) rat mutant, a spontaneous mutation leading to hair cell loss, deafness, impairment of vestibular functions, lateralized circling, hyperactivity and alterations in the nigrostriatal dopamine system, we have recently hypothesized that vestibular defects during postnatal development, independent of whether induced or inherited, lead to secondary changes in the dopaminergic system within the basal ganglia, which would be a likely explanation for the typical behavioral phenotype seen in such models. In the present study, we directly compared the phenotype induced by streptomycin in LEW rats with that of the ci2 LEW rat mutant. For this purpose, we treated neonatal LEW rats over 3 weeks by streptomycin, which induced bilateral degeneration of cochlear and vestibular hair cells. Following this treatment period, the behavioral syndrome of the streptomycin-treated animals, including the lateralized rotational behavior, was almost indistinguishable from that of ci2 mutant rats. However, in contrast to the ci2 mutant rat, all alterations, except the hearing loss, were only transient, disappearing between 7 and 24 weeks following treatment. In conclusion, in line with our hypothesis, vestibular defects induced in normal LEW rats led to the same phenotypic behavior as the inherited vestibular defect of ci2 mutant rats. However, with increasing time for recovery, adaptation to the vestibular impairment developed in streptomycin-treated rats, while all deficits persisted in the mutant animals. At least in part, the transient nature of the abnormal behaviors resulting from treatment with streptomycin could be explained by adaptation to the vestibular impairment by the use of visual cues, which is not possible in ci2 rats because of progressive retinal degeneration in these mutants. Although further experiments are needed to prove this hypothesis, the present study shows that direct comparisons between these two models serve to understand the mechanisms underlying the complex behavioral phenotype in rodents with vestibular defects and how these defects are compensated.
氨基糖苷类抗生素的临床应用因耳毒性而受到限制。在啮齿动物中，内耳损伤常与旋转行为和运动活动亢进有关，这让人联想到由前脑多巴胺系统失衡导致的此类行为。基于之前对转圈（ci2/ci2）刘易斯（LEW）大鼠突变体的观察，该自发突变导致毛细胞丧失、耳聋、前庭功能受损、向侧方转圈、活动亢进以及黑质纹状体多巴胺系统改变，我们最近推测，出生后发育过程中的前庭缺陷，无论其是诱导性的还是遗传性的，都会导致基底神经节内多巴胺能系统的继发性变化，这可能是此类模型中典型行为表型的一个合理解释。在本研究中，我们直接比较了链霉素在LEW大鼠中诱导的表型与ci2 LEW大鼠突变体的表型。为此，我们用链霉素对新生LEW大鼠进行了为期3周的治疗，这导致了耳蜗和前庭毛细胞的双侧退化。在此治疗期后，链霉素处理动物的行为综合征，包括向侧方旋转行为，与ci2突变大鼠的几乎无法区分。然而，与ci2突变大鼠不同的是，除听力丧失外，所有改变都是暂时的，在治疗后7至24周之间消失。总之，与我们的假设一致，正常LEW大鼠中诱导的前庭缺陷导致了与ci2突变大鼠遗传性前庭缺陷相同的表型行为。然而，随着恢复时间的增加，链霉素处理的大鼠对前庭损伤产生了适应性，而突变动物中所有缺陷都持续存在。链霉素治疗导致的异常行为的短暂性至少部分可以通过利用视觉线索来适应前庭损伤来解释，而在ci2大鼠中这是不可能的，因为这些突变体存在进行性视网膜退化。尽管需要进一步的实验来证实这一假设，但本研究表明，这两种模型之间的直接比较有助于理解具有前庭缺陷的啮齿动物复杂行为表型的潜在机制以及这些缺陷是如何得到补偿的。
