Neuromuscular Junction

Neuromuscular Junction
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Neuromuscular junctions are specialized synapses between a motor neuron and a muscle fiber.  Motor neurons transmit signals to muscle fibers and initiate muscle contraction through the release of acetylcholine (ACh). The pathophysiology of neuromuscular disorders can be diverse. Physiological function of the junction may be interrupted by an autoimmune response, such as the case with myasthenia gravis, or through toxins like botulinum toxin or many insecticides.

The Maestro Pro and Edge MEA systems have the ability to measure from both neurons and skeletal muscle simultaneously. Combined with the selective optical stimulation capabilities of the Lumos, an easy-to-use, scalable model of neuromuscular junction function can be achieved.

Controlling neuromuscular junction-mediated contractions with light
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The failure of the neuromuscular junction (NMJ) is a key component of degenerative neuromuscular disease, yet how NMJs degenerate in disease is unclear. With the ability to create relevant cell types from any genetic background, human induced pluripotent stem cells (hiPSCs) are a useful tool for disease modeling.  Here Swartz et al. present a scalable, hiPSC-derived co-culture system composed of independently derived spinal motor neurons (MNs) and skeletal myotubes (sKMs). In a model of C9orf72-associated disease, co-cultures form functional NMJs that can be manipulated through optical stimulation. Channel rhodopsin expressing motor neurons were able to elicit muscle contractions in the co-cultured sKMs when illuminated with blue light using the Lumos. Utilization of this co-culture model as a tunable, patient-derived system may offer significant insights into NMJ formation, maturation, repair, or pathogenic mechanisms that underlie NMJ dysfunction in disease.

Co-culture on a 4x4 array of electrodes

(A-B) Co-culture on a 4x4 array of electrodes. (C) Raster plot of the well shown in A-B during paced stimulation. Tick marks on the x-axis indicate light stimulation. Pink boxes represent evoked spike timeframe with bursts in blue. Electrode coordinates are labeled on the y-axis. (D) Quantification of electrode activity and network activity (E) during baseline and stimulated recordings. Dots represent individual wells. **, p < .01; ***, p < .001. (F) Decreased evoked spike counts following treatment with the gap junction blocker, heptanol treatment, which could be partially recovered with decreased concentration or washout (recovery). (G-H) Evoked spike counts were abolished with neuromuscular antagonists, decamethonium bromide and vecuronium. Data represented as the percent change per active electrode at baseline (untreated). (I) Model depicting co-cultures on MEAs. sKMs are plated on top of protein substrate and exist in an extracellular protein matrix [Swartz et al. (2020), Establishment of a Human Induced Pluripotent Stem Cell-Derived Neuromuscular Co-Culture Under Optogenetic Control. bioRxiv].

 

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