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Recognition and transmission: synaptic functions of recognition molecules| old_uid | 4610 |
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| title | Recognition and transmission: synaptic functions of recognition molecules |
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| start_date | 2008/04/14 |
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| schedule | 11h30 |
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| online | no |
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| summary | The neural cell adhesion molecule NCAM, a member of the immunoglobulin superfamily of cell adhesion molecules, is the only carrier of polysialic acid (PSA) in mammalian brains. At early stages of synaptogenesis in primary hippocampal cultures, clusters of NCAM at the cell surface – linked via spectrin to trans-Golgi network derived organelles - translocate along growing neurites to sites of neurite-to-neurite contacts within several minutes of initial contact formation. There, NCAM mediates an anchoring (“synaptic trap”) of the intracellular organelles. At later stages of synaptogenesis, the relative levels of postsynaptic NCAM expression control both the number and strength of synapses in an activity-dependent manner. This process requires polysialylation of NCAM and activity of FGF and NMDA receptors. In mature brains, NCAM is important for induction of NMDA receptor-dependent long-term potentiation (LTP) in the CA1, CA3 and dentate gyrus of the hippocampal formation, and several forms of learning and memory. To differentiate between the functions of PSA versus the extracellular domain of the NCAM glycoprotein backbone, we applied NCAM, PSA-NCAM, and PSA to acute slices of the hippocampal CA1 region of NCAM-deficient mice. Remarkably, both PSA and PSA-NCAM, but not NCAM restored normal LTP. Furthermore, contextual and tone memory in NCAM-deficient mice could be partially rescued by injection of PSA-NCAM, but not of NCAM, into the hippocampus, again highlighting the role of PSA. In vitro experiments demonstrate that PSA suppresses activation of NR2B-containing NMDA receptors by low concentrations of glutamate, suggesting that PSA may restrain activity of these receptors extrasynaptically. Thus, several mechanisms are emerging by which NCAM and associated PSA contribute to formation and plasticity of synapses.
Another member of the immunoglobulin superfamily of cell adhesion molecules is L1. Mice conditionally deficient in L1 after cessation of major developmental events show interesting impairment in autoassociative spatial memory. To investigate whether this phenotype is related to physiological changes in the hippocampus, we performed analysis of basal synaptic transmission and synaptic plasticity at synapses formed by (1) Schaffer collateral projections to the CA1 field; (2) lateral perforant path (LPP) and (3) medial perforant path (MPP) projections to the dentate gyrus; (4) direct perforant path projections to the CA3 and (5) CA1 fields; (6) associational/commissural and (7) mossy fiber projections to the CA3 field. Recordings in L1 deficient mice revealed that LTP is specifically impaired in synapses formed by perforant path fibers on apical distal dendrites of CA1 and CA3 pyramidal neurons. Pharmacological examination of the role of NMDA receptors and L-type voltage-dependent Ca2+ channels in induction of LTP at perforant path projections to the CA3 field showed that both of these molecules are involved in LTP, whereas the difference in LTP between wild-type and L1 deficient mice is mostly due to abnormal function of L-type Ca2+ channels. Thus, L1 appeared to regulate synaptic plasticity at synapses formed by entorhinal axons on distal dendrites of pyramidal neurons via modulation of L-type voltage-dependent Ca2+ channels. |
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| responsibles | Deris |
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