Conclusions And Future Directions

The data discussed in this chapter show that NCAM has "many faces" and is involved in many synaptic functions. Numerous in vitro, in situ, and in vivo studies have converged to demonstrate that 1) spatial and temporal patterns of NCAM and PSA expression is regulated by neuronal activity and animal experience; 2) learning and memory are affected by manipulation of NCAM and PSA; and 3) NCAM and PSA promote synaptogenesis and synaptic plasticity. The underlying mechanisms appear to be at least partially relevant to mechanisms underlying activity of NCAM during neurite outgrowth, which involve interaction with spectrin and signaling via the FGF receptor and fyn kinase. Currently, we know that spectrin is involved in stabilization of intracellular organelles during early synaptogenesis and that FGF receptors are required for synaptogenic activity of NCAM at later stages. However, the roles of FGF receptors, fyn kinase, and spectrin in NCAM-mediated synaptic plasticity have not yet been verified. Apart from these mechanisms, reported interactions between NCAM and glutamate receptors22 and a rescue of LTP deficits in NCAM-deficient mice by exogenous BDNF application20, suggest that new players may be specifically involved in the regulation of synaptic functions by NCAM, as compared to neuritogenesis.

Since PSA is involved in neuroplasticity, it is particularly interesting that there is a downregulation of polysialylated NCAM in the hippocampi of patients with schizophrenia75 and that a polymorphism in the promoter region of polysialyltransferase is associated with schizophrenia76. Additionally, soluble forms of NCAM are elevated in cerebrospinal fluid and in the brain of schizophrenic patients, whereas expression of the membrane-associated NCAM isoforms is unaffected77. These findings have stimulated an interest in soluble NCAM and a transgenic mouse (NCAM-EC) was recently generated, which overexpresses soluble NCAM in the brain63. NCAM-EC transgenic mice exhibit a striking reduction in synaptic puncta of GABAergic interneurons in several brain regions, as shown by decreased immunolabeling of GABAergic terminals. In addition, there is a reduction in excitatory synapses, as revealed by synaptophysin staining and apical dendritic spine density of cortical pyramidal cells, and expression of numerous behavioral abnormalities relevant to schizophrenia. Thus, understanding of mechanisms by which NCAM regulates synaptogenesis may guide us in finding effective treatments to compensate for abnormalities in synaptic connectivity in diseased brains.*

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