Purkinje cell long-term depression is prevented by T-588, a neuroprotective compound that reduces cytosolic calcium release from intracellular stores.
Long-term depression (LTD) of the parallel-fiber (PF) Purkinje synapse induced by four different experimental paradigms could be prevented in rat cerebellar slices by T-588, a neuroprotective compound. The paradigms consisted of pairing PF activation with climbing-fiber activation, direct depolarization, glutamic iontophoretic depolarization, or caffeine. In all cases, LTD was determined by patch-clamp recording of PF excitatory postsynaptic currents at the Purkinje cell somata. T-588 at 1 muM prevented the triggering of LTD reversibly and did not generate LTD on its own. Two-photon calcium-sensitive dye imaging demonstrated that T-588 reduces intracellular calcium concentration ([Ca(2+)](i)) increase by blocking calcium release from intracellular stores. Because [Ca(2+)](i) increase has been widely shown to trigger LTD and glutamate excitotoxicity, we propose that LTD may act as a neuroprotective mechanism. As such, LTD would serve to decrease glutamatergic-receptor sensitivity to limit deleterious [Ca(2+)](i) increase rather than to act as a mechanism for cerebellar learning.
Kimura
Tatsuo
T
Toyama Chemical Company, 2-4-1 Shimookui, Toyama 930-8508, Japan.
Sugimori
Mutsuyuki
M
Llinás
Rodolfo R
RR
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects* / Q000378:metabolism; D004048:Diethylamines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011689:Purkinje Cells / Q000187:drug effects* / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*
D000697:Central Nervous System Stimulants; D004048:Diethylamines; D018696:Neuroprotective Agents; D013876:Thiophenes; C082372:T 588; D002110:Caffeine; D002118:Calcium