Neuromuscular transmission and correlative morphology in young and old mice

Abstract

Age changes in spontaneous and evoked transmitter release, in receptor number and in ultrastructure at the neuromuscular junction were studied in the CBF-1 mouse strain, which stays physically active and relatively free of organ pathology into advanced age. Spontaneous miniature end-plate potentials (MEPP) were recorded in the following young (8-12 mo.) and old (29-33 mo.) mouse muscles: extensor digitorum longus (EDL), soleus (sol), gluteus maximus (GM), diaphragm (diaph) and extensor digitorum communis (EDC). MEPP amplitudes were unchanged with age in 4 muscle groups despite increases in input resistance (in EDL, sol and GM). MEPP amplitude in old diaph increased 54% with no change in input resitance. Bimodal distributions of MEPP amplitudes were observed in 6-23% of muscle fibers but were not more prevalent in old mice. There was little or no change in resting membrane potential with age. Numbers of junctional acetylcholine receptors (measured with 125I-.alpha.-bungarotoxin) were the same in all young and old muscles except EDL, where a 30% decrease was noted. Extrajunctional receptors and other indicators of denervation (decreases in resting potential, twitch tension or muscle fiber diameter) were absent or minimal. MEPP frequency decreased in EDL, sol and EDC but not in GM or diaph. There was no correlated change in the cholinesterase-positive end-plate area. MEPP amplitude is maintained in old muscles by a combination of compensatory changes. The decline in MEPP frequency varies between muscle groups and is independent of the length of the motoneuron axon or level of innervation. Ultrastructural morphometry was carried out in EDL. The nerve terminals in old (30 and 34 mo.) EDL muscles exhibited pronounced loss of synaptic vesicles. In 34-month animals, decreased nerve terminal area and post-synaptic folds devoid of nerve terminals were often observed. Since no evidence of denervation was found by physiological criteria, it is concluded that in 34-mo. mice, nerve terminals withdraw from some synaptic gutters but do not abandon any junction entirely. The large presynaptic ultrastructural changes contrast with the physiological data showing no deficit and even increases in transmitter release. Under these conditions, these profound structural changes are either not functionally significant or are well compensated.