Signalling mechanisms mediated by the phosphoinositide 3-kinase/Akt cascade in synaptic plasticity and memory in the rat.
The phosphoinositide 3-kinase (PI3K)/Akt signalling cascade has classically been implicated in promoting cell survival but more recently has been shown to regulate a number of other cellular functions. In particular, studies have suggested that PI3K contributes to mechanisms associated with synaptic plasticity and memory processes but the function of this cascade in forms of synaptic plasticity, such as long-term potentiation, remains controversial and the PI3K substrates which mediate these effects are poorly understood. Here we report that the PI3K inhibitor LY294002 infused i.c.v. in vivo blocked maintenance of long-term potentiation induced in the dentate gyrus with a single tetanus to the perforant path but not with repeated tetani. This pattern of stimulation led to rapid and transient phosphorylation of the PI3K substrate Akt at Ser473 but not at Thr308. Functional readout of partial activation of Akt was demonstrated by an increase in phosphorylation of two downstream substrates, Forkhead (FKHR) and mammalian target of rapamycin (mTOR), in a delayed and prolonged manner at Akt-specific phosphorylation sites. LY294002 blocked phosphorylation of Akt and the prolonged phosphorylation of FKHR and mTOR but did not impair long-term potentiation-induced phosphorylation of extracellular receptor kinase. In addition, the same i.c.v. concentration of LY294002 impaired long-term consolidation of recognition memory but not short-term recognition memory or spatial learning and repeated training in the recognition memory task overcame the deficit in consolidation. These results suggest that activation of the PI3K/Akt pathway may contribute to the mechanisms of synaptic plasticity and memory consolidation by promoting cell survival via FKHR and protein synthesis via mTOR. Importantly, only partial activation of Akt at its Ser473 residue was necessary to mediate these effects.
Horwood
Jennifer M
JM
Laboratoire de Neurobiologie de l'Apprentissage, de la Mémoire et de la Communication, CNRS UMR 8620, Université Paris Sud, Bat. 446, 91405 Orsay, France.
Dufour
Franck
F
Laroche
Serge
S
Davis
Sabrina
S
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002867:Chromones / Q000494:pharmacology*; D018891:Dentate Gyrus / Q000378:metabolism; D004594:Electrophysiology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D013912:Threonine / Q000378:metabolism; D000071161:Forkhead Box Protein O1
D002867:Chromones; D048049:Extracellular Signal-Regulated MAP Kinases; D051858:Forkhead Transcription Factors; D009025:Morpholines; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine; D058570:TOR Serine-Threonine Kinases; D013912:Threonine; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546845:mTOR protein, rat