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Figure 2.2. Mechanisms Regulating Synapse Formation in Various Model Preparations. (A) Lymnaea presynaptic neuron (visceral dorsal 4 - VD4 - fluorescently labeled with red dye, sulforhodamine) and postsynaptic neuron (left pedal dorsa 1 - LPeDl - injected with Lucifer yellow) were soma-soma paired. In this configuration, most molluscan neurons develop appropriate excitatory and inhibitory synapses similar to those seen in vivo. (B) An electron micrograph showing the nature of synaptic contacts between soma-soma paired neurons. Vesicles dock at presynaptic site juxtaposed against the postsynaptic cell (Figure courtesy of Dr. Matthias Amrein, University of Calgary). (C) Model depicting steps and mechanisms underlying trophic factor and target cell contact-induced synapse formation between Lymnaea neurons in a soma-axon configuration. The model predicts that both target cell contact and extrinsic trophic support are required for appropriate, excitatory synapse formation. See Colorplate 3.

However, the soma-soma model permitted the study of trophic factor's effects on synapse formation in the absence of neurite outgrowth. When paired in DM, inhibitory synapses between the identified neurons VD4 and RPeDl developed24. However, attempts to reconstruct excitatory synapses between VD4 and its other partner left pedal dorsal 1 (LPeDl) failed in DM. Under these experimental conditions, the neurons established inhibitory synapses, which were inappropriate and do not exist in vivo. In contrast, pairing in CM enabled appropriate excitatory synapses to develop between VD4 and LPeD1. This trophic factor-induced formation of excitatory synapses was mediated through receptor tyrosine kinases28,29. Similarly, the addition of trophic factors to pairs that developed inappropriate inhibitory synapses in DM resulted in a switch to appropriate excitatory synapses. This synapse switching also required receptor tyrosine kinase activity29,30. These findings have since been confirmed in the land snail Helix where appropriate, excitatory synapses were shown to rely upon the availability of specific trophic factors as well31. Utilizing novel synapses between soma-axon pairs (presynaptic soma paired with a somaless postsynaptic axon) from Lymnaea, it was subsequently shown that the trophic factor-induced excitatory synapse formation involves mobilization of excitatory, postsynaptic acetylcholine receptor from extrasynaptic to synaptic sites32. Together, these studies underscore the importance of trophic factor-mediated signaling in synapse formation and synaptic plasticity.

The precise identity of synapse-specific trophic molecules in Lymnaea is yet to be determined. However, the growth-promoting effects of human EGF (hEGF) on Lymnaea neurons led to the search for an EGF homolog in Lymnaea33. The Lymnaea albumen gland was found to be a rich source of Lymnaea EGF (L-EGF) and, when added to neurons in vitro, L-EGF exerted distinct growth-promoting effects on select neurons33. Addition of L-EGF to DM containing soma-soma28, and soma-axon pairs32 resulted in the formation of excitatory synapses, which were similar to those seen in CM. These results strongly indicate that L-EGF may be a major component of the CM-derived trophic factors that mediate excitatory synapse formation between paired neurons. However, L-EGF induces synapse formation between only 40% of the paired neurons28, thus the search continues for the remaining complement of synapse-specific factors present in CM.

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