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The Journal of Neuroscience, May 30, 2007, 27(22):6019-6028; doi:10.1523/JNEUROSCI.1022-07.2007

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Development/Plasticity/Repair
Hippocampal Metaplasticity Induced by Deficiency in the Extracellular Matrix Glycoprotein Tenascin-R

Olena Bukalo,¹ Melitta Schachner,^1,2 and Alexander Dityatev^1,3

¹Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, D-20251 Hamburg, Germany, ²Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, and ³Institut für Neurophysiologie und Pathophysiologie, Universitätsklinikum Hamburg-Eppendorf, D-20246 Hamburg, Germany

Correspondence should be addressed to Melitta Schachner, Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 85, D-20251 Hamburg, Germany. Email: melitta.schachner{at}zmnh.uni-hamburg.de

Predisposition of synapses to undergo plastic changes can be dynamically adjusted according to the history of synaptic activity (i.e., synapses are metaplastic). In search of a molecular mechanism underlying metaplasticity, we investigated mice deficient in the glycoprotein tenascin-R (TNR), based on the observations that this mutant exhibits elevated basal excitatory synaptic transmission and reduced perisomatic GABAergic inhibition. TNR is a major extracellular matrix glycoprotein of the CNS and carries the HNK-1 carbohydrate (human natural killer cell glycan), which has been identified as the functional epitope mediating regulation of GABAergic transmission via GABA_B receptors. Here, we used patch-clamp recordings in hippocampal slices to determine the critical levels of postsynaptic neuron depolarization necessary for induction of long-term potentiation (LTP) at CA3–CA1 synapses and found that deficiency in TNR leads to a metaplastic increase in the threshold for induction of LTP. Reconstitution of slices from TNR-deficient mice with an HNK-1 glycomimetic or pharmacological treatment with either a GABA_A receptor agonist, a GABA_B receptor antagonist, an L-type voltage-dependent Ca²⁺ channel blocker, or an inhibitor of protein serine/threonine phosphatases restored LTP to the levels seen in wild-type mice. We propose that a chain of events initiated by reduced GABAergic transmission and proceeding via Ca²⁺ entry into cells and elevated activity of phosphatases mediates homeostatic adjustment of hippocampal plasticity in the absence of TNR. These data uncover a novel mechanism by which an extracellular matrix molecule and its associated carbohydrate provide conditions beneficial for induction of LTP in the CA1 region of the hippocampus.

Key words: tenascin-R; knock-out mutant; extracellular matrix glycoprotein; hippocampus; long-term potentiation; CA1; metaplasticity

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Received March 7, 2007; revised April 11, 2007; accepted April 20, 2007.

Correspondence should be addressed to Melitta Schachner, Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 85, D-20251 Hamburg, Germany. Email: melitta.schachner{at}zmnh.uni-hamburg.de

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