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Alexander DityatevRecognition and transmission: synaptic functions of recognition molecules

Abstract :


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.     

Selected publications

Wijayawardhane N, Shonesy BC, Vaithianathan T, Pandiella N, Vaglenova J, Breese CR, Dityatev A, Suppiramaniam V. Ameliorating effects of preadolescent aniracetam treatment on prenatal ethanol-induced impairment in AMPA receptor activity.
Neurobiol Dis. 2008 Jan;29(1):81-91. Epub 2007 Aug 14.
Ponimaskin E, Voyno-Yasenetskaya T, Richter DW, Schachner M, Dityatev A.
Morphogenic signaling in neurons via neurotransmitter receptors and small GTPases.
Mol Neurobiol. 2007 Jun;35(3):278-87. Review.

Scientific focus :

Alexander Dityatev graduated in Mathematics at the Leningrad (St. Petersburg) State University in 1985. In 1991 he accomplished his PhD in Biology with a thesis on quantal analysis of glutamate release at the Sechenov Institute of Evolutionary Physiology and Biochemistry in Leningrad. In 1992-1996, he worked with Peter Clamann as a postdoctoral fellow at the Department of Physiology, University of Bern, where he studied relationships between the structure and function of synaptic connections in the spinal cord. He then worked with Melitta Schachner as a group leader at the Center for Molecular Neurobiology Hamburg. There he and his colleagues uncovered synaptic functions of several cell adhesion and extracellular matrix molecules, such as tenascins, chondroitin sulfate proteoglycans, NCAM, L1, CHL1, and their associated glycans, including HNK-1 and PSA. Many of these functions turned out to involve interplay between recognition molecules and ligand- or voltage gated ion channels, resulting in regulation of perisomatic GABAergic inhibition, hippocampal long-term potentiation/depression and contextual memory. In 2004-2007, Alexander Dityatev was a German Research Foundation (DFG) Fellow at the University Medical Center Hamburg-Eppendorf. Since 2006, he is affiliated Associate Professor at the Department of Pharmacal Sciences, Auburn University, with which he is closely collaborating to study modulation of glutamate receptors by glycans. He co-authored more than 70 papers in and co-edited with Alaa El-Husseini a book on “Molecular Mechanisms of Synaptogenesis”. Currently, he is a Senior Researcher at Italian Institute of Technology (IIT) and is working to identify recognition molecules involved in formation and maintenance of various subtypes of central synapses and to dissect recognition events and signal transduction cascades triggered or modulated via these molecules.

Dionysia Theodosis