Ncam And Synaptic Plasticity 51 Hippocampal Synaptic Plasticity

The first direct evidence that NCAM may play a role in synaptic plasticity was provided in 1994 by a seminal study that showed that perturbation of NCAM function significantly reduced LTP in the CA1 area of the hippocampus49; (see Chapter 25 for introduction in synaptic plasticity). Polyclonal antibodies against NCAM, soluble oligomannosides that block interaction of NCAM with oligomannosidic carbohydrates carried by L1, and synthetic peptides from the fourth Ig-like domain of NCAM, which mediates interaction with L1, were used in these experiments. Further studies using constitutive NCAM-knockout and conditionally NCAM-deficient mice, in which the NCAM gene is ablated in neurons after cessation of major developmental events, showed impairment of CA1 LTP in both mutants, thus supporting the view that NCAM plays acute functional role in synaptic plasticity in the CA1 region20,36,50. Additionally, LTD in the CA1 was impaired in conditional NCAM knockout mice50. In the CA3 region, constitutive NCAM but not conditional NCAM-deficient mice were found to have abnormalities in lamination of mossy fiber projections and to be impaired in mossy fiber LTP, suggesting that NCAM is required for proper development and function of mossy fiber-CA3 synapses50-52.

Since NCAM is the only carrier of PSA in mammalian brains, significant efforts were made to dissect the functions of PSA and the NCAM glycoprotein backbone. Enzymatic removal of PSA by endo-N inhibited LTP and LTP-associated formation of perforated synapses, and LTD in CA136,40,53. Experiments using mice deficient in one of two polysialyltransferases ST8SiaII (STX) or ST8SiaIV (PST), enzymes required for polysialylation of NCAM in immature and mature cells, respectively, provided the first genetic evidence for the importance of this carbohydrate in synaptic plasticity in the CA154'55. No involvement of these enzymes in mossy fiber LTP in the CA3 region was revealed, despite abnormal lamination of mossy fiber projections in STX-deficient mutants55. The first in vivo study5 demonstrated that mice deficient in either PST or STX also exhibited normal LTP in the dentate gyrus. However, this form of LTP was impaired in NCAM-/- mice56. Thus, NCAM is important for synaptic plasticity in the CA1, CA3 and dentate gyrus (Table 1).

Despite this intensive research, the mechanisms mediating NCAM action in synaptic plasticity are largely unknown. Since peptides blocking interaction of proteins with the fourth immunoglobulin-like domain of NCAM reduced LTP when applied before induction of LTP but not afterward57, a role of NCAM in LTP induction was suggested. Since impairment of LTP in NCAM-deficient mice could be rescued by elevation of extracellular Ca2+ concentration, one may speculate that NCAM influences Ca2+ entry via NMDA receptors50. Whether this is due to a reduced number of synaptic NMDA receptors or impaired function of these receptors remains to be determined. By analogy with the adhesion molecule neuroligin, which is connected indirectly via PSD-95 to NMDARs (Chapters 4 and 7), an indirect connection between the NCAM and the NMDARs seems possible. This is supported by the similar central location of NCAM180 and the NR2A within the postsynaptic density in untreated animals, and a similar redistribution of these molecules to the edges of postsynaptic density in animals after induction of LTP58. One of the scaffolding molecules cross-linking NCAM180 and NMDAR

Table 1. Effects of NCAM, PSA and Polysialyltransferases on Different Forms of Hippocampal Synaptic Plasticity.


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