Mechanisms of synaptic plasticity mediated by extracellular matrix glycoproteins of the tenascin family
Final Report Abstract
Our early in vitro studies revealed deficits in synaptic plasticity in the CA1 region of mice deficient in the extracellular matrix glycoproteins tenascin-C and tenascin-R. In frame of the present project we studied mechanisms underlying these abnormalities and extended analysis of synaptic plasticity to in vivo situation and to the CA3 region and dentate gyrus. Furthermore, we correlated observations from behavioral, electrophysiological and morphological studies to gain a more integrative view on functions of tenascins. In the CA1 region, we found that a chain of events initiated by reduced GABAergic transmission and proceeding via Ca2+ entry into cells and elevated activity of phosphatases mediates metaplastic/homeostatic adjustment of hippocampal plasticity in the absence of tenascin-R. In the dentate gyrus of tenascin-R deficient mice, we revealed reduced LTP, abnormally high ratio of inhibitory to excitatory cells, accompanied by increased perisomatic GABAergic input to granule cells. These features correlated with enhanced re-learning capabilities of mutants. Elevated number of S100-expressing astrocytes in this region of tenascin-R deficient mice correlated with slower epileptogenesis in the kindling model. In the CA1 region of tenascin-C mutants, we found a reduced Ca2+ influx via L-type voltage-dependent Ca2+ channels and presented evidence that abnormal levels of LTP can be restored by an agonist of L-type voltage-dependent Ca2+ channels. These physiological abnormalities correlated with impaired extinction of fear memory. Moreover, deficiency in tenascin-C occluded the effects of a blocker of L-type Ca2+ channels on extinction of fear memory, supporting the view that impairment in these channels underlies deficits in LTP and extinction in tenascin-C deficient mice. In summary, these studies not only uncovered new roles of tenascins, but also contributed to our understanding of processes underling synaptic plasticity, kindling, and relearning in mice.
Publications
- Bukalo O., and Dityatev A. (2006) Analysis of neural cell functions in gene knockout mice - electrophysiological investigation of synaptic plasticity in acute hippocampal slices. Methods in Enzymology 417: 52-66. Special issue: Functional Glycomics. Edited by Paulson J. and Fukuda M.
- Dityatev A, International Meeting on Polysialic Acids, Goslar, Germany, 2007.
- Dityatev A, International Neuroscience Winter Conference, Soelden, Austria, 2007.
- Dityatev A, International symposium "Development of Neurotransmitter Systems", Schoental, Germany, 2006
- Dityatev A., and Schachner M. (2006) The Extracellular Matrix and Synapses. Special issue: The Synapse: Structure and Function - Recent Advances. Cell Tissue Res. 326:647-654.
- Dityatev A., Frischknecht R., and Seidenbecher C. (2006) Extracellular matrix and synaptic functions. Results Probl. Cell Differ. 43: 69-97. Special issue: Cell Communication in Nervous and Immune System. Edited by Gundelfinger E., Seidenbecher C., and Schraven B.
- Dityatev A.E., and Bolshakov V.Y. (2005) Amygdala, LTP and fear conditioning. Neuroscientist 11: 75-88.
- Hammond M.S.L., Sims C., Parameshwaran K., Suppiramaniam V., Schachner M., and Dityatev A. (2006) NCAM associated polysialic acid inhibits NR2B-containing NMDA receptors and prevents glutamate-induced cell death. J. Biol. Chem. 281: 34859-34869. Highlight: von Elstermann M. Neuronal activity: Polysialic acid as a modulator of neurotransmission. Nature, Functional Glycomics Gateway, Nov. 2006.
- Morellini F., Lepsveridze E., Kähler B., Dityatev A., and Schachner M. (2007) Reduced reactivity to novelty, impaired social behavior, and enhanced basal synaptic excitatory activity in perforant path projections to the dentate gyrus in young adult mice deficient in the neural cell adhesion molecule CHL1. Mol. Cell. Neurosci. 34:121-36.
- Senkov O., Sun M., Weinhold B., Gerardy-Schahn R., Schachner M., and Dityatev A. (2006) Polysialylated NCAM is involved in induction of long-term potentiation and memory acquisition and consolidation in a fear conditioning paradigm. J. Neurosci. 26:10888-10898.
- Stoenica L., Senkov O., Weinhold B., Gerardy-Schahn R., Schachner M., and Dityatev A. (2006) In vivo synaptic plasticity in the dentate gyrus of mice deficient in the neural cell adhesion molecule NCAM or its polysialic acid. Eur. J. Neurosci. 23: 2255-2264.
