Neuromuscular Active Zone Structure and Function in Healthy and Lambert-Eaton Myasthenic Syndrome States

Abstract

The mouse neuromuscular junction (NMJ) has long been used as a model synapse for the study of neurotransmission in both healthy and disease states of the NMJ. Neurotransmission from these neuromuscular nerve terminals occurs at highly organized structures called active zones (AZs). Within AZs, the relationships between the voltage-gated calcium channels and docked synaptic vesicles govern the probability of acetylcholine release during single action potentials, and the short-term plasticity characteristics during short, high frequency trains of action potentials. Understanding these relationships is important not only for healthy synapses, but also to better understand the pathophysiology of neuromuscular diseases. In particular, we are interested in Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disorder in which neurotransmitter release from the NMJ decreases, leading to severe muscle weakness. In LEMS, the reduced neurotransmission is traditionally thought to be caused by the antibody-mediated removal of presynaptic voltage-gated calcium channels. However, recent experimental data and AZ computer simulations have predicted that a disruption in the normally highly organized active zone structure, and perhaps autoantibodies to other presynaptic proteins, contribute significantly to pathological effects in the active zone and the characteristics of chemical transmitters.

A Review on the Mechanisms of Stroke-Induced Muscle Atrophy

“…The neuromuscular junction plays an integral role in regulating the contractability activity of skeletal muscles since it is responsible for transmitting action potentials from the motor neurons to the muscle fibers. Changes in neuromuscular junction morphology, including nerve terminal size and the number of active zones, have been noted in multiple diseases including congenital myasthenic syndromes [68], myasthenia gravis [69] and Lambert-Eaton myasthenic syndrome [70]. However, there is little information regarding the role that stroke plays in affecting neuromuscular junction plasticity.…”

Early Alterations in Structural and Functional Properties in the Neuromuscular Junctions of Mutant FUS Mice

“…Neuromuscular transmission under normal external Ca 2+ levels relies on a release of several dozen up to a hundred acetylcholine quanta from a single NMJ [47]. Accordingly, evoked synaptic vesicle exocytosis occurs simultaneously in many active zones under normal extracellular Ca 2+ levels.…”