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

Abstract

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.

Neuronal substrates alter the migratory responses of nonmyelinating Schwann cells to controlled brain‐derived neurotrophic factor gradients

“…Neurodegeneration and dysfunction cause mobility impairment in millions of adults, worldwide. Contemporary regenerative therapies have begun to examine the NMJ as a therapeutic target to restore mobility via reestablished synaptic activity (Natarajan, Sethumadhavan, & Krishnan, ; Torres‐Espin, Beaudry, Fenrich, & Fouad, ). Studies have increasingly recognized terminal SCs as a critical component of the NMJ tripartite and synaptic structure (Figure ), as accumulating evidence illustrates that glia mediate the highly integrated behaviors of adult synapses.…”

How to Build and to Protect the Neuromuscular Junction: The Role of the Glial Cell Line-Derived Neurotrophic Factor

“…To better understand and prevent neurological disorders, the PNS, and particularly the NMJ, could represent an easy and accessible model to reveal what is occurring in the CNS. Strong experimental evidence throughout time and recently developed 3D neuromuscular models highlighted the great potential of NMJ as a reliable and non-invasive model to study mechanisms involved in synaptogenesis [ 4 ]. Indeed, different animal models have provided basic fundamental milestones for the understanding of the guidance of growth cones and motor axons toward their muscle targets (many examples come from studies in Drosophila, C. elegans or mouse).…”

Light Cross-Linkable Marine Collagen for Coaxial Printing of a 3D Model of Neuromuscular Junction Formation

“…Bioprinting technology offers the opportunity to fabricate in vitro tissue models by precisely positioning biomaterials and cells to create relevant tissue models for drug screening and disease modelling [ 67 ]. This in vitro model has wide applications in clinical research such as in the development of personalised therapies for neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) [ 68 ], investigations into the role of the synaptogenesis in neural degeneration [ 69 ], and as a drug testing platform. In this work, skeletal myoblasts and motor neuron cells were co-axially bioprinted to form a structured NMJ model in vitro.…”