Prior short-term synaptic disinhibition facilitates long-term potentiationand suppresses long-term depression at CA1 hippocampal synapses

Long-term potentiation (LTP) and long-term depression (LTD) are two main fo rms of activity-dependent synaptic plasticity that have been extensively st udied as the putative mechanisms underlying learning and memory. Current st udies have demonstrated that prior synaptic activity can influence the subs equent induction of LTP and LTD at Schaffer collateral-CA1 synapses. Here, we show that prior short-term synaptic disinhibition induced by type A gamm a-aminobutyric acid (GABA) receptor antagonist picrotoxin exhibited a facil itation of LTP induction and an inhibition of LTD induction. This effect la sted between 10 and 30 min after washout of picrotoxin and was specifically inhibited by the L-type voltage-operated Ca2+ channel (VOCC) blocker nimod ipine, but not by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-a mino-5-phosphopentanoic acid (D-APV). Moreover, this picrotoxin-induced pri ming effect was mimicked by forskolin, an activator of cyclic adenosine mon ophosphate (cAMP)-dependent protein kinase (PKA), and was blocked by the ad enylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 2253 6) and the PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-c AMPS), it was also found that following picrotoxin application, CA1 neurons have a higher probability of synchronous discharge in response to a popula tion of excitatory postsynaptic potential (EPSP) of fixed slope (EPSP/spike potentiation). However, picrotoxin treatment did not significantly affect paired-pulse facilitation (PPF). These findings suggest that a brief of GAB Aergic disinhibition can act as a priming stimulus for the subsequent induc tion of LTP and LTD at Schaffer collateral-CA1 synapses. The increase in Ca 2+ influx through L-type VOCCs in turn triggering a cAMP/PKA signalling pat hway is a possible molecular mechanism underlying this priming effect.