title: Persistent CaMKII activation mediates learning-induced long-lasting enhancement of synaptic inhibition.
abstract: Training rats in a particularly difficult olfactory-discrimination task results in acquisition of high skill to perform the task superbly, termed "rule learning" or "learning set." Such complex learning results in enhanced intrinsic neuronal excitability of piriform cortex pyramidal neurons, and in their excitatory synaptic interconnections. These changes, while subserving memory maintenance, must be counterbalanced by modifications that prevent overspreading of activity and uncontrolled synaptic strengthening. Indeed, we have previously shown that the average amplitude of GABAA-mediated miniature IPSCs (mIPSCs) in these neurons is enhanced for several days after learning, an enhancement mediated via a postsynaptic mechanism. To unravel the molecular mechanism of this long-term inhibition enhancement, we tested the role of key second-messenger systems in maintaining such long-lasting modulation. The calcium/calmodulin-dependent kinase II (CaMKII) blocker, KN93, significantly reduced the average mIPSC amplitude in neurons from trained rats only to the average pretraining level. A similar effect was obtained by the CaMKII peptide inhibitor, tatCN21. Such reduction resulted from decreased single-channel conductance and not in the number of activated channels. The PKC inhibitor, GF109203X, reduced the average mIPSC amplitude in neurons from naive, pseudo-trained, and trained animals, and the difference between the trained and control groups remained. Such reduction resulted from a decrease in the number of activated channels. The PKA inhibitor H89 dihydrochloride did not affect the average mIPSC amplitude in neurons from any of the three groups. We conclude that learning-induced enhancement of GABAA-mediated synaptic inhibition is maintained by persistent CaMKII activation.
authors.affiliation: Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel.
authors.forename: Sourav
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Reuveni
authors.affiliation: Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel.
authors.forename: Raphael
authors.initials: R
authors.lastname: Lamprecht
authors.affiliation: Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel ebarkai@research.haifa.ac.il.
authors.forename: Edi
authors.initials: E
authors.lastname: Barkai
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology; D012903:Smell / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000201:enzymology*
chemical_list: D007211:Indoles; D008301:Maleimides; D011963:Receptors, GABA-A; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C070515:bisindolylmaleimide I
keywords: olfactory learning; piriform cortex; pyramidal neurons; second messenger; synaptic inhibition