Presynaptic mechanism underlying cAMP-dependent synaptic potentiation.
The adenylyl cyclase activator forskolin presynaptically facilitates synaptic transmission at many synapses, but the exact intracellular mechanism underlying this effect is not known. We studied this issue at the calyx of Held, where it is possible to make simultaneous presynaptic and postsynaptic whole-cell recordings. Bath application of forskolin or intracellular application of cAMP into presynaptic terminals strongly potentiated EPSCs. The forskolin-induced synaptic potentiation was associated with increases in release probability (P) and number of releasable synaptic vesicles (N). Forskolin had no effect on the peak amplitudes of presynaptic Ca2+ currents or K+ currents, suggesting that the main target of cAMP resides in downstream of Ca2+ influx. Intracellular application of the selective Epac agonist 8-(4-chlorophenylthio)-2'-O-methyl-cAMP into presynaptic terminals potentiated EPSCs, suggesting that Epac is the main target of cAMP-induced synaptic potentiation. We conclude that an increase in cAMP concentration in the nerve terminal facilitates transmitter release by increasing both release probability and number of releasable vesicles via activating the Epac pathway at the calyx of Held.
Kaneko
Masahiro
M
Department of Neurophysiology, University of Tokyo Graduate School of Medicine, Tokyo 113-0033, Japan.
Takahashi
Tomoyuki
T
D000818:Animals; D001933:Brain Stem / Q000166:cytology / Q000502:physiology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000819:agonists; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D010703:Phorbol Esters / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013572:Synaptic Vesicles / Q000187:drug effects
D015220:Calcium Channels; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D020662:Guanine Nucleotide Exchange Factors; D010703:Phorbol Esters; D015221:Potassium Channels; D005576:Colforsin; D016291:Dizocilpine Maleate; D000242:Cyclic AMP