mTOR inhibitor rapamycin suppresses striatal post-ischemic LTP.
The two complexes of the mammalian target of rapamycin (mTOR), mTORC1 and mTORC2, have central functions in the integration of both extracellular and intracellular signals that are also critical players in the induction of post-ischemic long-term potentiation (i-LTP), a pathological form of plasticity inducible in striatal medium spiny neurons (MSNs) after a brief episode of in vitro ischemia. To evaluate the involvement of mTOR complexes during ischemia we analyzed the time course of i-LTP by intracellular recordings of MSNs from corticostriatal slices incubated with 1μM mTOR inhibitor rapamycin. Although rapamycin did not affect the amplitude and duration of ischemia-induced membrane depolarization it fully prevented i-LTP, leaving unaffected the capability to undergo activity-dependent LTP following high-frequency stimulation of corticostriatal fibers. The present results argue for a role of mTOR complex in i-LTP and suggest that rapamycin, by selectively blocking i-LTP, represents a promising therapeutic tool to limit cellular damage after ischemic brain insult.
Ghiglieri
Veronica
V
Fondazione Santa Lucia - IRCCS, via del Fosso di Fiorano, 64, 00143, Rome, Italy.
Pendolino
Valentina
V
Bagetta
Vincenza
V
Sgobio
Carmelo
C
Calabresi
Paolo
P
Picconi
Barbara
B
D000818:Animals; D001703:Biophysics; D002545:Brain Ischemia / Q000473:pathology*; D003342:Corpus Striatum / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D020123:Sirolimus