Basic NeuroscienceAn explant muscle model to examine the refinement of the synaptic landscape

- Use of innovative whole muscle explant system examining the dynamics of AChR cluster prepatterning.
- RyR1 activity and DHPR activity repress Wnt3a ability to eliminate aneural AChRs.
- RyR1 counteracts the ability of Agrin to aggregate AChR clusters.
- RyR1 is required for proper distribution of aneural and neuronal AChR clusters.
- PKA and CDK5 are molecular players within the muscle that control regionalization of aneural AChR clusters.

Signals from nerve and muscle regulate the formation of synapses. Transgenic mouse models and muscle cell cultures have elucidated the molecular mechanisms required for aggregation and stabilization of synaptic structures. However, far less is known about the molecular pathways involved in redistribution of muscle synaptic components. Here we established a physiologically viable whole-muscle embryonic explant system, in the presence or absence of the nerve, which demonstrates the synaptic landscape is dynamic and malleable. Manipulations of factors intrinsic to the muscle or extrinsically provided by the nerve illustrate vital functions during formation, redistribution and elimination of acetylcholine receptor (AChR) clusters. In particular, RyR1 activity is an important mediator of these functions. This physiologically relevant and readily accessible explant system provides a new approach to genetically uncouple nerve-derived signals and for manipulation via signaling molecules, drugs, and electrical stimulation to examine early formation of the neuromuscular circuit.