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MHC class I is required for activity-dependent structural remodeling at the developing neuromuscular junction

  • Author(s): McDonald, Marin Alisa
  • et al.
Abstract

Mature patterns of connectivity in the mammalian central and peripheral nervous systems require the selective elimination of redundant synaptic connections through activity-dependent mechanisms. At the developing neuromuscular junction (NMJ), individual muscle cells initially receive inputs from multiple motor neurons that are eliminated during the first two postnatal weeks until each motor endplate is monoinnervated. While the requirement for electrical activity in the normal progression of synapse elimination is well established, the underlying molecular mechanisms remain obscure. Here we identify proteins of the major histocompatibility complex class I (MHCI) as endogenous mediators of activity -dependent synapse elimination at the developing NMJ. MHCI protein is expressed at the NMJ during synapse elimination and genetic reduction of cell surface MHCI significantly increases the number of muscles that remain multiply innervated at the end of the remodeling period. Supernumerary inputs in MHCI-deficient animals are functional and persist into adulthood and the impairment of remodeling in MHCI-deficient animals is associated with a persistent increase in the mean amplitude of the miniature endplate potential (mEPP), suggesting that MHCI is required for the functional weakening of neuromuscular synapses. Additionally, acute blockade of MHCI function by in vivo injection of anti-MHCI antibodies is sufficient to impair developmental synapse elimination in wild type mice. These results provide new insights into the molecular basis of activity-dependent synapse elimination at the developing NMJ, and suggest that MHCI is part of a core mechanism of activity-dependent synapse remodeling that is conserved in the peripheral and central nervous systems

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