Tumor necrosis factor alpha mediates neuromuscular synapse elimination

Area of Science:

• Neuroscience
• Developmental Biology
• Cell Biology

Background:

• Neuromuscular junction (NMJ) development involves eliminating supernumerary axon inputs to ensure single innervation per muscle fiber.
• The molecular mechanisms driving this synaptic elimination process are not fully understood.

Purpose of the Study:

• To investigate the role of tumor necrosis factor-alpha (TNFα) in presynaptic axonal elimination at the mammalian NMJ.
• To determine if TNFα expressed by postsynaptic muscle cells mediates the removal of redundant synaptic inputs.

Main Methods:

• Intramuscular injection of TNFα into levator auris longus (LAL) muscles.
• Genetic ablation of TNFα in skeletal muscle cells, motoneurons, and Schwann cells.
• Analysis of presynaptic nerve terminal association with postsynaptic acetylcholine receptor (AChR) clusters.
• Utilizing a motoneuron-muscle coculture system to assess activity-dependent competition.

Main Results:

• Exogenous TNFα injection caused dissociation of presynaptic terminals from AChR clusters.
• Genetic ablation of TNFα in muscle cells significantly delayed synaptic elimination at the NMJ.
• TNFα ablation in muscle cells reduced activity-dependent competition in coculture systems.
• Ablation in motoneurons or Schwann cells did not affect synaptic elimination timing.

Conclusions:

• Postsynaptic TNFα plays a crucial role in the elimination of redundant presynaptic inputs at the NMJ.
• Muscle-derived TNFα is a key mediator of synaptic pruning during NMJ development.
• These findings identify a novel molecular pathway regulating synaptic refinement.