Synapse elimination in neonatal rat muscle is sensitive to pattern of muscle use

Abstract

The synaptic connections among the cells of the vertebrate nervous system undergo extensive rearrangements early in development^1,2. During their initial growth, neurones apparently form synaptic connections with an excessive number of targets, later retracting a portion of these synapses in establishing the adult neural circuits. Because of the profound effects which experience has upon the developing nervous system³, a question of considerable interest has been the role which the functional use of these developing synapses might play in determining the final pattern of connectivity. At the neuromuscular junction the early changes in synaptic connections are well documented, and here questions about the importance of function can be relatively easily addressed. Mammalian skeletal muscle fibres experience a perinatal period of synapse elimination so that all but one of several synapses formed on each muscle fibre are lost^4–6. This synapse elimination is sensitive to alterations of neuromuscular use or activity. Reduction of muscle use by tenotomy^7,8 or by paralysis of the muscle with drugs blocking nerve impulse conduction⁹ or neuromuscular transmission¹⁰ delays or even prevents synapse loss, while increased use produced by stimulation of the muscle nerve¹¹ apparently accelerates the rate at which synapses are lost. I report here a further examination of the role of neuromuscular activity in synapse elimination. I show that chronic neuromuscular stimulation accelerates synapse elimination but that this acceleration is dependent on the temporal pattern in which the stimuli are presented: brief stimulus trains containing 100 Hz bursts of stimuli produce this acceleration whereas the same number of stimuli presented continuously at 1 Hz do not. Furthermore, the 100 Hz activity pattern which is effective in altering synapse elimination also alters two other muscle properties: the sensitivity of the muscle fibres to acetylcholine and the ‘speed’ of muscle contractions. These findings suggest that the ability of muscle fibres to maintain more than one nerve terminal, like other muscle properties, is sensitive to the pattern of muscle use rather than just the total amount of use.