Nervous system functions in all animals rely upon synaptic connectivity that is established during early development. Whereas cell-cell signaling plays a critical role in establishing synapse specificity, the involvement of extrinsic growth factors cannot, however, be undermined. We have previously demonstrated that trophic factors are required for excitatory but not inhibitory synapse formation between Lymnaea neurons. Moreover, in the absence of trophic factors, neurons from a number of species establish inappropriate inhibitory synapses, which can, however, be corrected by the addition of trophic factors. The precise site of trophic factor actions (presynaptic versus postsynaptic) and the underlying mechanisms remain, however, undefined. Here, we provide the first direct evidence that the trophic factor-mediated excitatory synapse formation involves activity-induced calcium (Ca 2ϩ ) oscillations in the postsynaptic left pedal dorsal 1 (LPeD1) but not the presynaptic visceral dorsal 4 (VD4, cholinergic) neuron. These oscillations involved Ca 2ϩ influx through voltagegated Ca 2ϩ channels and required receptor tyrosine kinase activity which was essential for the expression of excitatory, nicotinic acetylcholine receptors in the postsynaptic cell during synapse formation. We also demonstrate that selectively blocking the electrical activity presynaptically did not perturb trophic factor-induced synapse formation between the paired cells, whereas hyperpolarizing the postsynaptic cell prevented appropriate synaptogenesis between VD4 and LPeD1 cells. Together, our data underscore the importance of extrinsic trophic factors in regulating the electrical activity of the postsynaptic but not the presynaptic cell and that the resulting Ca 2ϩ oscillations are essential for the expression of postsynaptic receptors during specific synapse formation.

First-degree relatives of patients with AMD tend to have a higher risk of AMD. Recognizing an inherent genetic risk of AMD in these patients will improve their management and potentially help prevent blindness.

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