Connectomic evidence that ordered activity drives neuromuscular network formation.

Area of Science:

• Neuroscience
• Developmental Biology
• Muscle Physiology

Background:

• Postnatal development involves significant synaptic reorganization in neuromuscular systems.
• Understanding the refinement of motor neuron connections to muscle fibers is crucial for grasping neural circuit formation.

Purpose of the Study:

• To reconstruct and analyze the complete connectomes between motor neurons and muscle fibers during mouse postnatal development.
• To investigate the mechanisms and activity-dependence of synaptic elimination and neuromuscular junction (NMJ) refinement.

Main Methods:

• Reconstruction of complete motor neuron-to-muscle fiber connectomes in mice from birth through postnatal development.
• Analysis of axonal branching, NMJ formation, and elimination dynamics.
• Correlation of synaptic elimination with axonal activity patterns and recruitment order.

Main Results:

• Axonal branching significantly decreased, leading to single innervation of all NMJs.
• Supernumerary NMJ sites on neonatal muscle fibers were largely eliminated, with few remaining in adults.
• Elimination of axons and NMJs was linked to the recruitment order of innervating axonal cohorts, indicating rank-ordered co-innervation.
• Remaining multi-NMJ fibers in adults showed widely separated junctions with similar activity patterns.

Conclusions:

• Synaptic competition at both local (intrajunctional) and long-distance (interjunctional) levels is primarily mediated by neural activity.
• The mature structure of neural circuits emerges from activity-driven patterns during development.
• Activity-dependent competition plays a key role in refining neuromuscular connectivity.