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 function can preserve youthful innervation of aging muscle.

Schwann cells participate in synapse elimination at the developing neuromuscular junction

“…Since a number of manipulations in addition to expression of NRG1-III can be shown to influence the rate of synapse elimination, control of synapse elimination is clearly multifactorial. Neuronal activity, as mentioned above, is clearly important [32–35]. There is evidence that NRG1 expression is itself influenced by the level of activity of neurons [36,37], suggesting a mechanism by which activity may lie upstream of NRG1-III regulation of tSCs.…”

Major Histocompatibility Complex I Expression by Motor Neurons and Its Implication in Amyotrophic Lateral Sclerosis

“…Motor neurons seem to be the most responsive in triggering the MHCI during normal aging ( 34 , 35 ), after insults such as the axotomy ( 36 ) or ventral horn root avulsion ( 37 ) or during chronic diseases such as experimental autoimmune encephalomyelitis in mice ( 38 ). We recently reported that spinal motor neurons of transgenic mice carrying the mutant SOD1 G93A markedly activated the expression of several molecules associated with MHCI at the onset and during the progression of the disease ( 39 – 41 ).…”

Tumor necrosis factor alpha mediates neuromuscular synapse elimination

“…Interestingly, several classes of immune molecules, including C1q, the initiating protein in the classical complement cascade, and MHCI, play important roles in developmental synapse elimination [61][62][63][64] . Although synapse elimination at the NMJ occurred normally in mice deficient for pivotal protein of the complement cascade C3 61 , MHCI appeared to be involved 23 . In addition, glutamatergic transmission via N-methyl-Daspartate (NMDA) receptors seemed to be involved in the Fig.…”

“…Recently, some retrograde factors, such as BDNF/proBDNF or Sama3A/Sama7A, expressed by postsynaptic cells are found to mediate presynaptic axonal elimination 15,[18][19][20][21][22] . In addition, class I major histocompatibility complex (MHCI) has been reported to be involved in developmental synapse elimination at the NMJ 23,24 . Nevertheless, the molecular and cellular mechanisms regulating the competitions among nerve terminals on one single muscle fiber remain largely unknown.…”