Progression of age changes in synaptic transmission at mouse neuromuscular junctions.

Abstract

SUMMARY1. The progression of age-related changes in neuromuscular function was investigated in muscles from CBF-1 mice between 7 and 32 months of age. End-plate potentials (e.p.p.s) were recorded in extensor digitorum longus (e.d.l.), soleus, and diaphragm muscles after neuromuscular transmission was blocked with either (+ )-tubocurarine chloride (curare) or high-Mg/low-Ca Krebs solutions.2. Between 10 and 31 months of age in e.d.l. and soleus but not in diaphragm, there was an increase in e.p.p. amplitude with age. In soleus this increase was approximately two-fold in curare and three-fold in high-Mg solution.3. Increase in e.p.p. amplitude in curarized preparations took place between 20 and 28 months of age in e.d.l. and between 28 and 31 months of age in soleus.4. Indirectly elicited twitch responses were used to determine the time course of age-related changes in sensitivity to Mg block. Increased resistance to block appeared between 15 and 19 months of age in-both e.d.l. and soleus (in which the increase was more gradual).5. E.d.l. muscles from 25-month-old CFW mice also showed an increased resistance to Mg block compared to those from 7-8-month-old animals.6. In Mg-blocked preparations, increased quantum content (measured directly) accounted for the increased e.p.p. amplitude. Spontaneous miniature end-plate potential (m.e.p.p.) frequency in old soleus muscles was not sensitive to low-Ca/highMg solutions although frequency in young soleus and young and old diaphragm was significantly reduced.7. It is concluded that age-related changes in evoked transmitter release begin in mid life and take place more rapidly in e.d.l. than in soleus. This may be due to the difference in muscle type or to the different usage of these muscles. In both muscles, age changes appear before any significant mortality or organ pathology is evident. Decreased sensitivity of transmitter release to low Ca/high Mg is therefore an early sign of altered synaptic transmission in ageing mouse muscle.

Increased motor unit potential shape variability across consecutive motor unit discharges in the tibialis anterior and vastus medialis muscles of healthy older subjects

“…Increases in quantal release of neurotransmitter, as demonstrated by increased evoked endplate potential amplitudes, has been shown in mice . These changes are correlated with studies reporting a decrease in the number of synaptic vesicles, nerve terminal area, acetylcholine receptors, and number of post-synaptic folds with aging (Courtney and Steinbach, 1981;Robbins, 1982, 1986;Banker et al, 1983;Fahim et al, 1983;Kelly and Robbins, 1983;Jang and Van Remmen, 2011). While this increase in neurotransmitter release may seem like an effective compensatory strategy for age-related morphological changes, it has been suggested this actually results in an increased rate of neuromuscular transmission failure (Manini et al, 2013).…”

Age-associated alterations of the neuromuscular junction

“…Along with changes in the morphology of the NMJ, age-related changes in the quantal content of neurotransmitter release have also been reported in mouse EDL and soleus muscle between 10 and 32 months of age in CBF-1 mice (Kelly and Robbins, 1983, 1986). These changes in quantal release, measured as increases in amplitude of evoked endplate potentials (EPP), were correlated with a decrease in the number of synaptic vesicles, a decrease in nerve terminal area, and a decrease in the number of post-synaptic folds lacking nerve terminals.…”

Effects of enhanced activity on synaptic transmission in mouse extensor digitorum longus muscle.

“…It has been reported previously that transmitter release and junctional size increase with ageing in some muscles but not in others (Kelly & Robbins, 1983;Robbins & Fahim, 1985;Cardasis & LaFontaine, 1987); interestingly, continuously active muscles like the diaphragm showed no differences in either parameter throughout adulthood indicating that maintained activity might maintain junctional characteristics. Effects on endplate structure and function of abnormal patterns of activity achieved with electrical stimulation of motoneurons have previously been reported (Atwood & Lnenicka, 1987;Hinz & Wernig, 1988;Dorl6chter, Braden, Langenfeld & Wernig, 1989; see also Lomo & Waerhaug, 1985); elevated activity with a tonic stimulus pattern imposed over several days onto phasic muscles apparently caused depression in initial transmitter release but increased facilitation, or tetanic potentiation.…”