title: Hippocampal metaplasticity induced by deficiency in the extracellular matrix glycoprotein tenascin-R.
abstract: 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.
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, D-20251 Hamburg, Germany.
authors.forename: Olena
authors.initials: O
authors.lastname: Bukalo
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.forename: Alexander
authors.initials: A
authors.lastname: Dityatev
mesh_terms: D000818:Animals; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D006624:Hippocampus / Q000502:physiology*; D017774:Long-Term Potentiation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics; D019063:Tenascin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D016326:Extracellular Matrix Proteins; D019063:Tenascin; C074638:tenascin R