Presynaptic Activity and CaMKII Modulate Retrograde Semaphorin Signaling and Synaptic Refinement

SummaryEstablishing synaptic connections often involves the activity-dependent withdrawal of off-target contacts. We describe an in vivo role for temporally patterned electrical activity, voltage-gated calcium channels, and CaMKII in modulating the response of Drosophila motoneurons to the chemorepellent Sema-2a during synaptic refinement. Mutations affecting the Sema-2a ligand, the plexin B receptor (plexB), the voltage-gated Ca(v)2.1 calcium channel (cac), or the voltage-gated Na(v)1 sodium channel (mlenap-ts;tipE) each result in ectopic neuromuscular contacts. Sema-2a interacts genetically with both of the channel mutations. The cac phenotype is enhanced by the Sema-2a mutation and is suppressed by either plexB overexpression or patterned, low-frequency (0.01 Hz) bouts of electrical activity in the embryo. The calcium-dependent suppression of ectopic contacts also depends on the downstream activation of CaMKII. These results indicate a role for patterned electrical activity and presynaptic calcium signaling, acting through CaMKII, in modulating a retrograde signal during the refinement of synaptic connections.

► Presynaptic activity modulates Sema2a signaling to remove erroneous contacts
► Synaptic refinement requires patterned presynaptic activity every 2–3 min
► The response to Sema-2a depends on Ca entry via Ca(v)2.1 channels and CaMKII