Development of a novel in vitro model system to characterize the role of activity in motor neurons during development and disease
Neural activity modulates motor axon guidance and synaptic function during development. Differences in neural activity also contribute to the demise of specific motor neuron subtypes in amyotrophic lateral sclerosis (ALS). Studying the cellular mechanisms underlying these activity-dependent processes is complicated due to the inability to precisely activate motor neurons separate from other cell types. Here, we resolve this issue by generating embryonic stem cell-derived motor neurons (ESCMNs) expressing channelrhodopsin-2 (ChR2). ChR2 ESCMNs depolarize and fire single action potentials when pulsed by light. Chronic light activation of ChR2 ESCMNs (0.025 Hz for 2 days) increases neurite outgrowth, mediated by enhanced expression of polysialylated NCAM (PSA-NCAM). ChR2 ESCMNs expressing SOD1G93A, a mutation causing ALS, form neuromuscular junctions in vitro, but unlike wild-type counterparts, fail to maintain functional connections over time. Together, this thesis introduces a novel model system to study cellular mechanisms underlying activity-dependent modulation of motor neuron development and disease.
- Motor neuron disease
- Amyotrophic Lateral Sclerosis
- Neural Activity
- Neural Cell Adhesion Molecule
- Polysialic Acid
- Neurite Outgrowth
- Activity dependent
- Light Activation
- Neuromuscular junction
- Embryonic Stem Cells
- Embryonic Stem Cell derived motor neurons
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