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 Projects

 Synaptic Glycoproteins

K.-H. Smalla, N. Höche, K. Pohlmann, W. Tischmeyer

Many glycoproteins are major constituents of synaptic membranes. Posttranslational modifications like protein glycosylation are widely accepted to be of crucial importance for synaptic communication (e.g. Matthies et al. 1999). In particular terminal modifications of carbohydrate chains by fucose and/or sialic acid have been shown to be critical requirements for hippocampal long-term potentiation (LTP) and long-term memory formation. Furthermore, application of fucose significantly enhances LTP maintenance in vivo and in vitro (Krug et al. 1994; Matthies et al. 1997; Matthies et al. 2000). Thus our studies are focussing on the identification of synaptic glycoproteins and the functional significance of their glycan moieties, for synaptic plasticity. We use affinity chromatographic techniques based on fucose-specific antibodies or lectins to identify fucosylated proteins. This approach revealed that several synaptic proteins are fucosylated. These include NCAM 180, NCAM 140, N-Cadherin and Neuroplastin (Smalla et al. 1998).

Lectinhistochemical staining of rat hippocampus

Fig. 1:  Lectinhistochemical staining of rat hippocampal slices with close-up of CA1 (upper right), CA3 (bottom left) and dentate gyrus (bottom right) areas. (Courtesy of Dr. K. Richter, OvGU)

In collaboration with D.C. Dieterich (OvGU), our current research aims at an in-depth characterization of synaptic fucosylproteins with a special focus on differential changes in the fucosylation of proteins related to synaptic plasticity. Using “click chemistry” (Dehnert et al. 2011, ACS Chem Biol 6:547-52) in combination with immunochemical and lectinchemical techniques, we are now able to detect activity-dependent alterations of protein fucosylation. Fig. 2 shows cultured hippocampal neurons incubated in azido-(L)-fucose under either control conditions (left) or conditions that activate NMDA-type glutamate receptors to induce synaptic plasticity (right). Utilising copper-catalyzed azido-alkyne (3+2) cycloaddition of alkyne-TexasRed to azido-fucose, the newly incorporated fucose derivative can be detected with fluorescence microscopy.

Fig. 2: Incorporated azido-(L)-fucose visualized with TexasRed in primary cultured hippocampal neurons (div 21) 48 h after stimulation with 20 µM NMDA/10 µM Glycin for 5 minutes (right panel) compared to a saline-treated control (left panel).

Collaborations:

Relevant Publications:

Krug, M., Wagner, M., Staak, S. Smalla, K.H. (1994) Fucose and fucose-containing sugar epitopes enhance hippocampal long-term potentiation in the freely moving rat. Brain Res. 643, 130-135.

Matthies, H. Jr., Staak, S., Smalla, K.H. , Krug, M. (1997) Enhancement if hippocampal long-term potentiation in vitro by fucosyl-carbohydrates. In: Neurochemistry: Cellular, Molecular and Clinical Aspects; Eds A. Teelken and J. Korf, Plenum Press 1997, New York and London, 905-908

Smalla, K.H. , Angenstein, F., Richter, K., Gundelfinger, E.D. and Staak, S. (1998) Identification of fucose-alpha[1-2]-galactose epitope-containing glycoproteins from rat hippocampus. NeuroReport 9 , 813-817

Matthies,H. Jr., Kretlow, J,,Matthies, H., Smalla, K.H. , taak, S., Krug, M. (1999) Glycosylation of proteins during a critical time window is necessary for the maintenance of long-term potentiation in the hippocampal CA1 region. Neuroscience 91 , 175-183

Matthies, H., Schröder, H., Smalla, K.H. and Krug, M. (2000) Enhancement of glutamate release by L-fucose changes effects of glutamate receptor antagonists on long-term potentiation in the rat hippocampus. Learning & Memory 7 , 227-234

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