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Muscle-wide secretion of a miniaturized form of neural agrin rescues focal neuromuscular innervation in agrin mutant mice.

ABSTRACT: Agrin and its receptor MuSK are required for the formation of the postsynaptic apparatus at the neuromuscular junction (NMJ). In the current model the local deposition of agrin by the nerve and the resulting local activation of MuSK are responsible for creating and maintaining the postsynaptic apparatus including clusters of acetylcholine receptors (AChRs). Concomitantly, the release of acetylcholine (ACh) and the resulting depolarization disperses those postsynaptic structures that are not apposed by the nerve and thus not stabilized by agrin-MuSK signaling. Here we show that a miniaturized form of agrin, consisting of the laminin-binding and MuSK-activating domains, is sufficient to fully restore NMJs in agrin mutant mice when expressed by developing muscle. Although miniagrin is expressed uniformly throughout muscle fibers and induces ectopic AChR clusters, the size and the number of those AChR clusters contacted by the motor nerve increase during development. We provide experimental evidence that this is due to ACh, because the AChR agonist carbachol stabilizes AChR clusters in organotypic cultures of embryonic diaphragms. In summary, our results show that agrin function in NMJ development requires only two small domains, and that this function does not depend on the local deposition of agrin at synapses. Finally, they suggest a novel local function of ACh in stabilizing postsynaptic structures.

SUBMITTER: Lin S

PROVIDER: S-EPMC2497462 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPeripheral magnetic stimulation (PMS) is emerging as a complement to standard electrical stimulation (ES) of the peripheral nervous system (PNS). PMS may stimulate sensory and motor nerve fibers without the discomfort associated with the ES used for standard nerve conduction studies. The PMS coils are the same ones used in transcranial magnetic stimulation (TMS) and lack focality and selectiveness in the stimulation.PurposeThis study presents a novel coil for PMS, developed using Flexible technologies, and characterized by reduced dimensions for a precise and controlled targeting of peripheral nerves.MethodsWe performed hybrid electromagnetic (EM) and electrophysiological simulations to study the EM exposure induced by a novel miniaturized coil (or mcoil) in and around the radial nerve of the neuro-functionalized virtual human body model Yoon-Sun, and to estimate the current threshold to induce magnetic stimulation (MS) of the radial nerve. Eleven healthy subjects were studied with the mcoil, which consisted of two 15 mm diameter coils in a figure-of-eight configuration, each with a hundred turns of a 25 μm copper-clad four-layer foil. Sensory nerve action potentials (SNAPs) were measured in each subject using two electrodes and compared with those obtained from standard ES. The SNAPs conduction velocities were estimated as a performance metric.ResultsThe induced electric field was estimated numerically to peak at a maximum intensity of 39 V/m underneath the mcoil fed by 70 A currents. In such conditions, the electrophysiological simulations suggested that the mcoil elicits SNAPs originating at 7 mm from the center of the mcoil. Furthermore, the numerically estimated latencies and waveforms agreed with those obtained during the PMS experiments on healthy subjects, confirming the ability of the mcoil to stimulate the radial nerve sensory fibers.ConclusionHybrid EM-electrophysiological simulations assisted the development of a miniaturized coil with a small diameter and a high number of turns using flexible electronics. The numerical dosimetric analysis predicted the threshold current amplitudes required for a suprathreshold peripheral nerve sensory stimulation, which was experimentally confirmed. The developed and now validated computational pipeline will be used to improve the performances (e.g., focality and minimal currents) of new generations of mcoil designs.

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Muscle-wide secretion of a miniaturized form of neural agrin rescues focal neuromuscular innervation in agrin mutant mice.

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