Role of NCAM in Mammalian Synaptogenesis

The role of NCAM in formation of hippocampal synapses was established in 200035. Since NCAM is expressed both pre- and postsynaptically, we used heterogenotypic co-cultures of wild-type (NCAM+/+) and NCAM-deficient (NCAM-/-) neurons to dissect roles that pre- and postsynaptic NCAM may play in synaptic functions. Using this system, double-cell patch-clamp recordings of unitary excitatory postsynaptic currents (uEPSCs) in NCAM+/+ and NCAM-/-neurons (evoked by intracellular stimulation of NCAM+/+ or NCAM-/-presynaptic neurons) were performed. Comparison of the mean amplitudes of uEPSPs in synaptic connections with different patterns of NCAM expression revealed that the presence of NCAM presynaptically did not influence synaptic strength, whereas postsynaptic expression of NCAM increased synaptic strength by a factor of 2. Paired-pulse facilitation and amplitude of miniature EPSPs were normal in NCAM-/- neurons, suggesting that the probability of release and postsynaptic response elicited by release of a single vesicle are not affected by the absence of NCAM. Also, no changes in size of NCAM-/- neurons were found. However, analysis of synaptophysin immunoreactivity associated with NCAM-/-and NCAM+/+ neurons revealed a 2-fold higher synaptic coverage of NCAM+/+ cells, measured as the number of synaptophysin-rich puncta or as the mean intensity of synaptophysin immunofluorescence. This was observed only in heterogenotypic cultures, i.e., under conditions when growing axons have a choice which postsynaptic target to select: NCAM+/+ or NCAM-/-. There was no difference between NCAM-/- and NCAM+/+ neurons in synaptic coverage in homogenotypic cultures. Thus, expression of NCAM dictates where to form synapses, but is not required for synapse formation. Evidently, the absence of NCAM in NCAM-/- cultures can be compensated by other molecules. Since expression of NCAM and PSA in the CNS is regulated in an activity-dependent manner36-39 an increase in NCAM/PSA-NCAM expression may promote experience-dependent synaptogenesis in stimulated neurons and/or dendritic subdomains (Figure 6.2; Colorplate 5).

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