Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases

The addition or loss of synapses in response to changes in activity, diseas e, or aging is a major aspect of nervous system plasticity in the adult. Th e mechanisms that affect the turnover and maintenance of synapses in the ad ult are poorly understood and are difficult to investigate in the brain. He re, we exploited a unique anatomical arrangement in the neuromuscular syste m to determine whether subtypes of synapses can differ in anatomical plasti city and vulnerability. In three genetic mouse models of motoneuron disease of diverse origin and severity, we observed a gradual and selective loss o f synaptic connections that begun long before the onset of clinical deficit s and correlated with the timing of disease progression. A subgroup of fast -type (fast-fatiguable) neuromuscular synapses was highly vulnerable and wa s lost very early on. In contrast, slow-type synapses resisted up to the te rminal phase of the disease. Muscle-specific differences were also evident. Similar selective losses were detected in aged mice. These selective vulne rability properties of synapses coincided with hitherto unrecognized major differences in stimulus-induced anatomical plasticity that could also be re vealed in healthy mice. Using paralysis and/or growth-associated protein 43 overexpression to induce synaptic sprouting, we found that slow-type, dise ase-resistant synapses were particularly plastic. In contrast, fast-type sy napses with the highest vulnerability failed to exhibit any stimulus-induce d change. The results reveal pronounced subtype specificity in the anatomic al plasticity and susceptibility to loss of neuromuscular synapses and sugg est that degenerative motoneuron diseases involve a common early pathway of selective and progressive synaptic weakening also associated with aging.