ABSTRACT
Administration of the Group 1 metabotropic glutamate receptor (mGluR) agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) facilitates ("primes") subsequent long-term potentiation (LTP) through a phospholipase C signaling cascade that may involve release of Ca2+ from the endoplasmic reticulum (ER). We investigated the intracellular calcium pathways involved in this priming effect, recording field potentials from area CA1 of rat hippocampal slices before and after high-frequency stimulation. The priming of LTP by DHPG was prevented by co-administration of cyclopiazonic acid, which depletes ER Ca2+ stores. The priming effect was also blocked by the ryanodine receptor (RYR) antagonist ryanodine (RYA, 100 microM). In contrast, a low dose of RYA (10 microM) which opens the RYR channel, by itself primed LTP. In addition to RYR activation, entry of extracellular calcium through store-operated channels appears necessary for priming, since diverse treatments known to impede store-operated channel activity completely blocked both RYA and DHPG priming effects. Thus, RYR activation plays a critical role in the priming of LTP by Group 1 mGluRs, and this effect is coupled to the entry of extracellular calcium, probably through store-operated calcium channels.
Subject(s)
Hippocampus/physiology , Long-Term Potentiation/physiology , Ryanodine Receptor Calcium Release Channel/metabolism , Animals , Boron Compounds/pharmacology , Calcium/metabolism , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Drug Interactions , Electric Stimulation/methods , Enzyme Inhibitors/pharmacology , Excitatory Amino Acid Agonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Excitatory Postsynaptic Potentials/radiation effects , Hippocampus/drug effects , Hippocampus/radiation effects , In Vitro Techniques , Indoles/pharmacology , Long-Term Potentiation/drug effects , Long-Term Potentiation/radiation effects , Male , Methoxyhydroxyphenylglycol/analogs & derivatives , Methoxyhydroxyphenylglycol/pharmacology , Nitriles , Patch-Clamp Techniques/methods , Rats , Rats, Sprague-Dawley , Ryanodine/pharmacology , Tyrphostins/pharmacologyABSTRACT
The ability of priming activation of metabotropic glutamate receptors (mGluRs) to regulate long-term depression (LTD) was studied in area CA1 of hippocampal slices taken from young adult male rats. Pharmacological activation of Group I mGluRs 30-40 min prior to low-frequency stimulation at 3 Hz failed to affect LTD. Activation of Group II mGluRs, however, significantly inhibited the LTD by >50%, while activation of Group III mGluRs had no statistically significant effect on LTD. The inhibition of LTD by activation of Group II mGluRs was even stronger when the Group II agonist was applied during the low-frequency stimulation. Because activation of Group II mGluRs is also known to inhibit LTP, the net effect of such stimulation is the induction of a metaplasticity that greatly restricts the effective range of stimuli that can evoke synaptic plasticity in the hippocampus.