Toward Building the Neuromuscular Junction: In Vitro Models To Study Synaptogenesis and Neurodegeneration

[Image: see text] The neuromuscular junction (NMJ) is a unique, specialized chemical synapse that plays a crucial role in transmitting and amplifying information from spinal motor neurons to skeletal muscles. NMJ complexity ensures closely intertwined interactions between numerous synaptic vesicles, signaling molecules, ion channels, motor neurons, glia, and muscle fibers, making it difficult to dissect the underlying mechanisms and factors affecting neurodegeneration and muscle loss. Muscle fiber or motor neuron cell death followed by rapid axonal degeneration due to injury or disease has a debilitating effect on movement and behavior, which adversely affects the quality of life. It thus becomes imperative to study the synapse and intercellular signaling processes that regulate plasticity at the NMJ and elucidate mechanisms and pathways at the cellular level. Studies using in vitro 2D cell cultures have allowed us to gain a fundamental understanding of how the NMJ functions. However, they do not provide information on the intricate signaling networks that exist between NMJs and the biological environment. The advent of 3D cell cultures and microfluidic lab-on-a-chip technologies has opened whole new avenues to explore the NMJ. In this perspective, we look at the challenges involved in building a functional NMJ and the progress made in generating models for studying the NMJ, highlighting the current and future applications of these models.