The First Model Synapse
To understand how synapses form, scientists turned to a giant, accessible example: the neuromuscular junction (NMJ), where motor neurons meet muscle fibers and use acetylcholine as a transmitter.
Before a neuron arrives, acetylcholine receptors (AChRs) are spread across the muscle surface. When the motor axon contacts the muscle, something remarkable happens: AChRs cluster at the future synapse.
Agrin: The Clustering Signal
Work by McMahan and Sanes pinpointed the signal. They showed that the basal lamina at the synaptic site holds a synaptogenic factor produced by the nerve: Agrin. Agrin binding activates the MuSK receptor, which signals through rapsyn to cluster AChRs. In agrin knockout mice, synapse formation is severely disrupted.
Nearby muscle nuclei also change their behavior. As shown by Fischbach and colleagues, nuclei close to the NMJ selectively transcribe AChR subunits, a process regulated by neuregulins. The result is a highly specialized patch of postsynaptic membrane.
From Many Inputs to One
During development, each muscle fiber is initially innervated by multiple motor neurons. Over time, this redundancy is pruned. Experiments show that partial receptor blockade can cause corresponding presynaptic terminals to retract, highlighting the role of activity-dependent competition.
Connectomic analysis of entire motor-unit circuits revealed just how extensive this remodeling is: a tenfold decrease in synapse number as axons prune many connections while expanding others at remaining NMJs.
Synapses in the Brain
In the central nervous system, the rules are similar but the cast of molecules changes. Agrin seems less central. Neurons cultured in vitro still form synapses reminiscent of those in vivo, indicating that synaptogenic signals are robust and often intrinsic.
CNS studies have focused heavily on glutamatergic synapses. Time-lapse imaging shows dendritic filopodia reaching out to contact axons; these contacts then recruit postsynaptic proteins and mature into synapses. Astrocytes also promote synaptogenesis—factors in glial-conditioned media strongly induce synapse formation in retinal ganglion cells, implicating unknown astrocytic signals.
Molecules like neuroligins and SynCAM can induce presynaptic differentiation. Neuroligins cluster at postsynaptic sites and signal via neurexins on presynaptic axons, while SynCAM acts as an adhesion molecule present on both sides of the synapse.
The Takeaway
Synapse formation is a carefully choreographed dialogue. Whether at a muscle fiber or in cortex, nerves and their partners exchange molecular cues, compete, and remodel until stable, efficient communication points emerge.