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J Neurosci. 2007 May 30;27(22):6019-28.

Hippocampal metaplasticity induced by deficiency in the extracellular matrix glycoprotein tenascin-R.

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Zentrum f├╝r Molekulare Neurobiologie, Universit├Ątsklinikum Hamburg-Eppendorf, D-20251 Hamburg, Germany.


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.

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