Mediator protein complex subunit 12 (Med12) is a core component of the basal transcriptional apparatus and plays a critical role in the development of many tissues. Mutations in Med12 are associated with X-linked intellectual disability syndromes and hearing loss; however, its role in nervous system function remains undefined. Here, we show that temporal conditional deletion of Med12 in astrocytes in the adult CNS results in region-specific alterations in astrocyte morphology. Surprisingly, behavioral studies revealed rapid hearing loss after adult deletion of Med12 that was confirmed by a complete abrogation of auditory brainstem responses. Cellular analysis of the cochlea revealed degeneration of the stria vascularis, in conjunction with disorganization of basal cells adjacent to the spiral ligament and downregulation of key cell adhesion proteins. Physiologic analysis revealed early changes in endocochlear potential, consistent with strial-specific defects. Together, our studies reveal that Med12 regulates auditory function in the adult by preserving the structural integrity of the stria vascularis.

SIGNIFICANCE STATEMENT Mutations in Mediator protein complex subunit 12 (Med12) are associated with X-linked intellectual disability syndromes and hearing loss. Using temporal-conditional genetic approaches in CNS glia, we found that loss of Med12 results in severe hearing loss in adult animals through rapid degeneration of the stria vascularis. Our study describes the first animal model that recapitulates hearing loss identified in Med12-related disorders and provides a new system in which to examine the underlying cellular and molecular mechanisms of Med12 function in the adult nervous system.

介质蛋白复合物亚基 12 (Med12) 是基础转录装置的核心成分，在许多组织的发育中起着关键作用。Med12 中的突变与 X 连锁智力障碍综合征和听力损失有关；然而，它在神经系统功能中的作用仍未确定。在这里，我们展示了成人中枢神经系统星形胶质细胞中 Med12 的时间条件缺失导致星形胶质细胞形态的区域特异性改变。令人惊讶的是，行为研究显示成人删除 Med12 后听力迅速丧失，这通过听觉脑干反应的完全取消得到证实。耳蜗的细胞分析显示血管纹退化，结合螺旋韧带附近基底细胞的解体和关键细胞粘附蛋白的下调。生理学分析揭示了耳蜗电位的早期变化，与 strial 特异性缺陷一致。总之，我们的研究表明 Med12 通过保持血管纹的结构完整性来调节成人的听觉功能。

重要性声明Mediator 蛋白复合物亚基 12 (Med12) 的突变与 X 连锁智力障碍综合征和听力损失有关。在中枢神经系统胶质细胞中使用时间条件遗传方法，我们发现 Med12 的丧失通过血管纹的快速退化导致成年动物的严重听力损失。我们的研究描述了第一个重述 Med12 相关疾病中发现的听力损失的动物模型，并提供了一个新系统，可以在其中检查 Med12 功能在成人神经系统中的潜在细胞和分子机制。