Tetruashvily Mazell M, McDonald Marin A, Frietze Karla K, Boulanger Lisa M
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, United States; Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States.
Department of Neurosciences, University of California, San Diego 92093, United States; Medical Scientist Training Program, University of California, San Diego 92093, United States.
Brain Behav Immun. 2016 Aug;56:197-208. doi: 10.1016/j.bbi.2016.01.008. Epub 2016 Jan 21.
Synapse elimination at the developing neuromuscular junction (NMJ) sculpts motor circuits, and synapse loss at the aging NMJ drives motor impairments that are a major cause of loss of independence in the elderly. Here we provide evidence that at the NMJ, both developmental synapse elimination and aging-related synapse loss are promoted by specific immune proteins, members of the major histocompatibility complex class I (MHCI). MHCI is expressed at the developing NMJ, and three different methods of reducing MHCI function all disrupt synapse elimination during the second postnatal week, leaving some muscle fibers multiply-innervated, despite otherwise outwardly normal synapse formation and maturation. Conversely, overexpressing MHCI modestly accelerates developmental synapse elimination. MHCI levels at the NMJ rise with aging, and reducing MHCI levels ameliorates muscle denervation in aged mice. These findings identify an unexpected role for MHCI in the elimination of neuromuscular synapses during development, and indicate that reducing MHCI levels can preserve youthful innervation of aging muscle.
发育中的神经肌肉接头（NMJ）处的突触消除塑造了运动回路，而衰老的NMJ处的突触丧失会导致运动功能障碍，这是老年人失去独立能力的主要原因。在这里，我们提供证据表明，在NMJ处，发育性突触消除和与衰老相关的突触丧失均由特定的免疫蛋白——主要组织相容性复合体I类（MHCI）的成员所促进。MHCI在发育中的NMJ处表达，三种不同的降低MHCI功能的方法均会破坏出生后第二周的突触消除，使一些肌纤维受到多重神经支配，尽管突触形成和成熟在其他方面看似正常。相反，过表达MHCI会适度加速发育性突触消除。NMJ处的MHCI水平随衰老而升高，降低MHCI水平可改善老年小鼠的肌肉去神经支配。这些发现确定了MHCI在发育过程中消除神经肌肉突触方面的意外作用，并表明降低MHCI水平可以保留衰老肌肉的年轻神经支配。
