title: MHCI promotes developmental synapse elimination and aging-related synapse loss at the vertebrate neuromuscular junction.
abstract: 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.
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, United States; Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States.
authors.forename: Mazell M
authors.initials: MM
authors.lastname: Tetruashvily
authors.affiliation: Department of Neurosciences, University of California, San Diego 92093, United States; Medical Scientist Training Program, University of California, San Diego 92093, United States.
authors.forename: Marin A
authors.initials: MA
authors.lastname: McDonald
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, United States.
authors.forename: Karla K
authors.initials: KK
authors.lastname: Frietze
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ 08544, United States; Department of Neurosciences, University of California, San Diego 92093, United States; Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544, United States. Electronic address: lboulang@princeton.edu.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Boulanger
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D005805:Genes, MHC Class I / Q000502:physiology*; D051379:Mice; D009469:Neuromuscular Junction / Q000254:growth & development / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*
keywords: Aging; Denervation; Development; MHCI; Major histocompatibility complex class I; NMJ; Neuromuscular junction; Synapse elimination