LRP4 is critical for neuromuscular junction maintenance.

Area of Science:

• Neuroscience
• Muscle Biology
• Synaptic Plasticity

Background:

• The neuromuscular junction (NMJ) is vital for muscle contraction.
• Agrin-LRP4-MuSK signaling is crucial for NMJ formation.
• The role of LRP4 in NMJ maintenance in adults was unclear due to perinatal lethality of null mutations.

Purpose of the Study:

• To investigate the role of LRP4 in the maintenance of the adult NMJ.
• To determine the consequences of LRP4 gene ablation in adult muscle.

Main Methods:

• Generated inducible knockout (imKO) mice (LRP4 imKO) allowing doxycycline-inducible deletion of LRP4 in adult muscles.
• Administered doxycycline to P30 mice to ablate LRP4.
• Assessed muscle strength, compound muscle action potentials, acetylcholine receptor (AChR) cluster integrity, junctional folds, synaptic vesicles, and miniature endplate potentials.

Main Results:

• Doxycycline treatment led to reduced muscle strength and compound muscle action potentials.
• AChR clusters fragmented, with diminished junctional folds and synaptic vesicles.
• Reduced amplitude and frequency of miniature endplate potentials indicated impaired neuromuscular transmission.
• LRP4 ablation caused loss of synaptic agrin and its fragments, preceding other synaptic component loss.
• LRP4 appears to regulate synaptic agrin stability.

Conclusions:

• LRP4 is essential for maintaining the structural and functional integrity of the adult NMJ.
• Loss of muscle LRP4 in adulthood is sufficient to cause myasthenic symptoms.
• LRP4 plays a critical role in stabilizing synaptic agrin at the NMJ.