dizocilpine-maleate and tributyl-phosphate

Hippocampal long-term potentiation (LTP) induced by theta-burst pairing of Schaffer collateral inputs and postsynaptic firing is associated with localized increases in synaptic strength and dendritic excitability. Using the same protocol, we now demonstrate a decrease in cellular excitability that was blocked by the h-channel blocker ZD7288. This decrease was also induced by postsynaptic theta-burst firing alone, yet it was blocked by NMDA receptor antagonists, postsynaptic Ca2+ chelation, low concentrations of tetrodotoxin, omega-conotoxin MVIIC, calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitors and a protein synthesis inhibitor. Increasing network activity with high extracellular K+ caused a similar reduction of cellular excitability and an increase in h-channel HCN1 protein. We propose that backpropagating action potentials open glutamate-bound NMDA receptors, resulting in an increase in I(h) and a decrease in overall excitability. The occurrence of such a reduction in cellular excitability in parallel with synaptic potentiation would be a negative feedback mechanism to normalize neuronal output firing and thus promote network stability.

Topics: 2-Amino-5-phosphonovalerate; Animals; Animals, Newborn; Blotting, Western; Calcium; Calcium Channel Blockers; Cardiovascular Agents; Cyclic Nucleotide-Gated Cation Channels; Diagnostic Imaging; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Hippocampus; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; In Vitro Techniques; Ion Channels; Long-Term Potentiation; Male; Membrane Potentials; Neurons; omega-Conotoxins; Organophosphates; Patch-Clamp Techniques; Potassium Channels; Potassium Chloride; Pyrimidines; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Statistics, Nonparametric; Tetrodotoxin; Time Factors