Goodrich Lisa, Franco Joy, Copeland Taylor, Merrow Ryan
Harvard Medical School.
Res Sq. 2025 Sep 1:rs.3.rs-7437264. doi: 10.21203/rs.3.rs-7437264/v1.
Neuronal subtype-specific synaptopathy is a hallmark of many forms of neurodegeneration. We examined the cellular basis for synaptic vulnerability in the auditory system, where three subtypes of spiral ganglion neurons (SGNs)-Ia, Ib, and Ic-carry acoustic information from the cochlea to the brain. In response to noise and aging, a subset of synapses between inner hair cells and SGNs are lost, but it is unclear how this loss varies across SGN subtypes. Using genetic labelling, we showed that Ia SGNs have larger post-synaptic densities (PSDs) than Ib and Ic SGNs and are the most resilient subtype. Ia PSD volumes increased with age and were unchanged after noise exposure. By contrast, average Ib/Ic PSD volumes did not change with age but decreased with noise. Genetic reprogramming of Ib/Ic neurons to a Ia-like identity provided significant protection against noise-induced synaptopathy, linking identity to resilience and providing an entry point for therapeutics.
神经元亚型特异性突触病变是多种神经退行性疾病的一个标志。我们研究了听觉系统中突触易损性的细胞基础，在该系统中，螺旋神经节神经元（SGNs）的三种亚型——Ia、Ib和Ic——将来自耳蜗的声学信息传递至大脑。响应噪声和衰老，内毛细胞与SGNs之间的一部分突触会丧失，但尚不清楚这种丧失在不同SGN亚型之间如何变化。利用基因标记，我们发现Ia SGNs比Ib和Ic SGNs具有更大的突触后致密物（PSD），并且是最具弹性的亚型。Ia PSD体积随年龄增长而增加，噪声暴露后保持不变。相比之下，Ib/Ic PSD的平均体积不随年龄变化，但随噪声而减小。将Ib/Ic神经元基因重编程为类似Ia的特性可显著保护其免受噪声诱导的突触病变，将特性与弹性联系起来，并为治疗提供了一个切入点。
