Protein phosphatases mediate depotentiation induced by high-intensity theta-burst stimulation.
We have previously reported that varying stimulus intensity produces qualitatively different types of synaptic plasticity in area CA1 of hippocampal slices: brief low-intensity (LI) theta-burst (TB) stimuli induce long-term potentiation (LTP), but if the stimulus intensity is increased (to mimic conditions that may exist during seizures), LTP is not induced; instead, high-intensity (HI) TB stimuli erase previously induced LTP ("TB depotentiation"). We now have explored the mechanisms underlying TB depotentiation using extracellular field recordings with pharmacological manipulations. We found that TB depotentiation was blocked by okadaic acid and calyculin A (inhibitors of serine/threonine protein phosphatases PP1 and PP2A), FK506 (a specific blocker of calcineurin, a Ca(2+)/calmodulin (CaM) protein phosphatase), and 8-Br-cAMP (an activator of protein kinase A) with 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor). These results suggest that protein phosphatase pathways are involved in the TB depotentiation similar to other type of down-regulating synaptic plasticity such as low-frequency stimulation (LFS)-induced long-term depression (LTD) and depotentiation in the rat hippocampus. However, TB depotentiation and LFS depotentiation could have differential functional significance.
Kang-Park
Maeng-Hee
MH
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Sarda
Meredith A
MA
Jones
Katherine H
KH
Moore
Scott D
SD
Shenolikar
Shirish
S
Clark
Suzanne
S
Wilson
Wilkie A
WA
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000201:enzymology*; D008297:Male; D008387:Marine Toxins; D008564:Membrane Potentials / Q000502:physiology; D019319:Okadaic Acid / Q000494:pharmacology; D009924:Organ Culture Techniques; D010080:Oxazoles / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013826:Theta Rhythm; D014970:Xanthines / Q000494:pharmacology
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D010080:Oxazoles; D010726:Phosphodiesterase Inhibitors; D014970:Xanthines; D019319:Okadaic Acid; D015124:8-Bromo Cyclic Adenosine Monophosphate; C059041:calyculin A; C051360:1,3-dipropyl-8-cyclopentylxanthine; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D015056:1-Methyl-3-isobutylxanthine