The level of reduction in synapse number seen with transient cadherin blockade in the first week of culture is on par with that reported following shRNA knockdown of neuroligins-1, -2, and -3 at similar maturational stages15'66. Although the morphological criteria used to identifying synapses in these studies differ, these findings collectively suggest that cadherins have some synaptogenic capacities. To date, only SynCAM and members of the neurexin/neuroligin families are thought to be capable of initiating synapse formation, based on their abilities to cluster axonal vesicles and induce glutamatergic transmission between neurons and nonneuronal cells in heterologous cultures46,67 (see Chapters 7 and 8). Notably, the non-neuronal HEK293 cells used in these studies express endogenous cadherins. Thus, it is possible that cadherins act coordinately with these and other cell-adhesion molecules' to form normal synapses. Beyond general synapse formation, the synaptogenic properties of cadherins appear to have been appropriated in adulthood to impart networks with dynamic control of synapse maintenance, strengthening and signaling. Recent work suggests this function is likely to be critical for maintaining normal cognitive capacity. Presenilin-1 can regulate the strength of cadherin adhesion and participates in the y-secretase mediated e-cleavage of n-cadherin. The liberated intracellular fragment can enter the nucleus and negatively regulate the activity of the transcription factor CREB (cyclic AMP response element binding protein) which controls the expression of certain genes critical for nervous system function and plasticity. Mutations in presenilin-1 that are known to be involved in early onset familial Alzheimer's disease prevent N-cadherin cleavage suggesting a link between the regulation of cadherin adhesion, transcriptional regulation and cognition12.''

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