In vivo imaging shows loss of synaptic sites from neuromuscular junctions in a model of myasthenia gravis.

Abstract

We examined the pre- and postsynaptic elements of the neuromuscular junction during immune attack on the postsynaptic acetylcholine receptors (AChRs) in a model of myasthenia gravis (MG). We followed, in the sternomastoid muscle of living mice, the staining of nerve terminals and postsynaptic AChRs at individual neuromuscular junctions in situ for up to 16 days after exposure to a monoclonal anti-AChR antibody. Several exposures to this antibody over 6 days led to spotty loss of AChR staining 1 to 3 days later within individual neuromuscular junctions. In addition, we observed loss of motor nerve terminal staining at presynaptic sites opposed to postsynaptic regions that had lost AChRs. Sites that lost pre- and postsynaptic staining were often immediately adjacent to other junctional regions that maintained a high density of AChRs and still stained presynaptically. Ultimately, the loss of synaptic sites resulted in neuromuscular junctions that appeared to be abnormally fragmented. To determine whether junctions recovered from the immune attack, we followed some antibody-treated muscle fibers for an additional 8 days without further exposure to antibody. Signs of recovery were evident because some of the synaptic regions that had previously lost AChRs subsequently regained them. But these junctions still remained fragmented both pre- and postsynaptically. These findings suggest that the postsynaptic membrane is affected in a highly local way by the immune attack on AChRs occurring in MG. One consequence of this attack is a long-term loss of not only postsynaptic components but also the overlying nerve terminals.