Persistence of Neuromuscular Junctions after Axotomy in Mice with Slow Wallerian Degeneration (C57BL/Wld^s)

Abstract

The present study was undertaken to examine the fate of neuromuscular junctions in C57BVWldS mice (formerly known as O M mice) after nerve injury. When a peripheral nerve is injured, the distal axons normally degenerate within 1-3 days. For motor axons, an early event is deterioration of motor nerve terminals at neuromuscular junctions. Previously, the vulnerability of motor terminals has been attributed either to a 'signal' originating at the site of nerve injury and transported rapidly to the terminals or to their continual requirement for essential maintenance factors synthesized in the motor neuron cell body and supplied to the terminals by fast axonal transport. Mice of the WldS strain have normal axoplasmic transport but show an abnormally slow rate of axon and myelin degeneration. Structure and function are retained in the axons of distal nerve stumps for several days or even weeks after nerve injury in these mice. The results of the present study show that WldS neuromuscular junctions are also preserved and continue to release neurotransmitter and recycle synaptic vesicle membrane for at least 3 days and in some cases up to 2 weeks after nerve injury. Varying the site of the nerve lesion delayed degeneration by -1-2 days per centimetre of distal nerve remaining. These findings suggest that the mechanisms of nerve terminal degeneration after injury are more complex than can be accounted for simply by the failure of motor neuron cell bodies to supply their terminals with essential maintenance factors. Rather, the data support the view that nerve section normally activates cellular components or processes already present, but latent, in motor nerve endings, and that in WldS mice either the trigger or the cellular response is abnormal.

Neuroprotection after Transient Global Cerebral Ischemia in Wlds Mutant Mice

“…Alternatively, the demonstration that Wld can alter cerebral metabolism and, more specifically, significantly reduce levels of cytosolic glutamate supports an effect of Wld on neurotransmitter levels (Tsao et al, 1999). However, peripheral nerve axotomy leads, within a few days, to accelerated spontaneous transmitter release from presynaptic motor nerve terminals of mice or rats expressing the Wld gene (Ribchester et al, 1995;Ribchester RR, Thomson D, Coleman MP, 2003). It will therefore be of great interest to establish whether increases in the extracellular levels of neurotransmitters are delayed or reduced in Wld-expressing mice after ischemia.…”

Differential protection of neuromuscular sensory and motor axons and their endings in Wld mutant mice

“…We tested first whether axotomised distal sen-sory (afferent) axons in Wld S mice show persistent endog-enous residual activity. Propagated centripetal (efferent) motor activity terminates at the site of a peripheral nerve lesion in motor axons, so the distal axons are silent in vivo even though the distal stumps and neuromuscular junc-tions remain physiologically competent to conduct action potentials and release neurotransmitter (Tsao et al, 1994;Ribchester et al, 1995;Gillingwater et al, 2002). But afferent activity, of course, originates in sensory receptors distal to the lesion: including muscle, joints and skin.…”

Nerve–Muscle Interactions

“…Many of the convergent synapses are subsequently eliminated, but significant numbers of endplates retain a persistent poly neuronal innervation (Barry & Ribchester, 1995). Vital staining with the activitydependent styryl dyes FMl-43 and RH414 reveals a diversity of form at these endplates: variable fractional occupancy of the end plate is shown by the converging inputs (from 1 to 50%).…”

“…Axotomy either in vivo or in vitro leads to gradual retraction of synaptic boutons and a decline in their quantal content, in a fashion that resembles synapse elimination (Ribchester et al 1995;Parson et al 1998). This system may provide a useful paradigm for investigating mechanisms of non-competitive synapse elimination ('intrinsic withdrawal') , a component of synapse elimination that has been somewhat neglected of late (Fladby & Jansen, 1987).…”