Different phosphatase-dependent mechanisms mediate long-term depression and depotentiation of long-term potentiation in mouse hippocampal CA1 area.
Two types of synaptic depression have been described in the hippocampus, long-term depression and depotentiation of long-term potentiation known to recruit the serine/threonine protein phosphatases PP1, PP2A and PP2B (calcineurin). The contribution of each of these protein phosphatases is controversial. To examine the role of the Ca2+/calmodulin-dependent protein phosphatase calcineurin in long-term depression and depotentiation, we analysed the effect of genetically inhibiting calcineurin reversibly in the hippocampus, using the doxycycline-dependent rtTA system in transgenic mice. We show that reducing calcineurin activity has no effect on long-term depression but reversibly affects depotentiation. Consistently, the calcineurin inhibitor FK-506 reproduces the depotentiation impairment observed in the mutant mice but does not affect long-term depression in control animals. In contrast, the PP1/PP2A inhibitor okadaic acid fully blocks both long-term depression and depotentiation. These data demonstrate that the nature of signalling cascades induced by synaptic activity depends on the initial synaptic state. While depression of potentiated synaptic responses requires activation of PP1/PP2A and/or calcineurin, depression of basal synaptic responses depends only on PP1/PP2A activation.
Jouvenceau
Anne
A
INSERM U549, Paris, France Institute of Cell Biology, Department of Biology, ETH Zürich, Switzerland.
Billard
Jean-Marie
JM
Haditsch
Ursula
U
Mansuy
Isabelle M
IM
Dutar
Patrick
P
D000818:Animals; D004558:Electric Stimulation; D004594:Electrophysiology / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000033:anatomy & histology / Q000502:physiology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D019319:Okadaic Acid / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000145:classification / Q000502:physiology*; D017729:Presynaptic Terminals / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D019319:Okadaic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D010744:Phosphoric Monoester Hydrolases; D016559:Tacrolimus