PDF(Pubmed)
Abstract：
AMPA-type glutamate receptors (AMPAR) mediate excitatory cochlear transmission. However, the unique roles of AMPAR subunits are unresolved. Lack of subunit GluA3 (Gria3KO) in male mice reduced cochlear output by 8-weeks of age. Since Gria3 is X-linked and considering sex differences in hearing vulnerability, we hypothesized accelerated presbycusis in Gria3KO females. Here, auditory brainstem responses (ABR) were similar in 3-week-old female Gria3WT and Gria3KO mice. However, when raised in ambient sound, ABR thresholds were elevated and wave-1 amplitudes were diminished at 5-weeks and older in Gria3KO. In contrast, these metrics were similar between genotypes when raised in quiet. Paired synapses were similar in number, but lone ribbons and ribbonless synapses were increased in female Gria3KO mice in ambient sound compared to Gria3WT or to either genotype raised in quiet. Synaptic GluA4:GluA2 ratios increased relative to Gria3WT, particularly in ambient sound, suggesting an activity-dependent increase in calcium-permeable AMPARs in Gria3KO. Swollen afferent terminals were observed by 5-weeks only in Gria3KO females reared in ambient sound. We propose that lack of GluA3 induces sex-dependent vulnerability to AMPAR-mediated excitotoxicity.
摘要：
AMPA型谷氨酸受体(AMPAR)介导兴奋性耳蜗传递。然而,AMPAR亚基的独特作用尚未解决。雄性小鼠中GluA3亚基（Gria3KO）的缺乏使8周龄的耳蜗输出减少。由于Gria3是X连锁的，并且考虑到听力脆弱性的性别差异，我们假设Gria3KO雌性的老年性耳聋加速。这里,3周龄雌性Gria3WT和Gria3KO小鼠的听觉脑干反应(ABR)相似.然而,当在环境声音中升起时，在Gria3KO中，ABR阈值升高，并且第1波振幅在5周及以上时减小。相比之下,当安静时，这些指标在基因型之间相似。配对的突触数量相似，但是，与Gria3WT或安静培养的任一基因型相比，雌性Gria3KO小鼠在环境声音中的孤带和无带突触增加。突触GluA4：GluA2比率相对于Gria3WT增加，特别是在环境声音中，提示Gria3KO中钙通透性AMPAR的活性依赖性增加。仅在环境声中饲养的Gria3KO雌性中观察到5周的肿胀传入末端。我们建议缺乏GluA3会诱导性别依赖性对AMPAR介导的兴奋性毒性的脆弱性。
