Requirement of a critical period of GABAergic receptor blockade for induction of a cAMP-mediated long-term depression at CA3-CA1 synapses

Abstract

Previous reports show that bath application of the adenosine 3′ : 5′‐cyclic monophosphate (cAMP) analog, Sp‐cAMPS, induces a protein kinase A (PKA)‐dependent and protein synthesis‐dependent long‐term potentiation (LTP) at hippocampal CA3‐CA1 synapses. Recently, we reported a novel form of long‐term depression (LTD) induced by concurrent application of Sp‐cAMPS and picrotoxin, the γ‐aminobutyric acid type A (GABA_A) receptor antagonist. In the present study, we further investigated the mechanisms underlying such cAMP‐mediated LTD. Synaptically connected CA3 and CA1 cells of hippocampal slice cultures were impaled by sharp electrodes. Excitatory postsynaptic potentials recorded from a CA1 pyramidal cell were evoked by single action potentials in a CA3 cell. Picrotoxin was applied to slices at various time points after Sp‐cAMPS was perfused. We found that Sp‐cAMPS‐induced potentiation could be converted to depression when picrotoxin was applied within 30 min after perfusion of Sp‐cAMPS. Picrotoxin applied 1 h after perfusion of Sp‐cAMPS had no effect on Sp‐cAMPS‐induced synaptic potentiation. Once LTP was induced by Sp‐cAMPS and expressed for 1 h, the subsequent application of Sp‐cAMPS and picrotoxin produced no new changes in synaptic strength. Also, once LTD was induced and expressed for 1 h, subsequent Sp‐cAMPS produced no new changes in synaptic strength. These findings suggest that a synapse is committed irreversibly to cAMP‐mediated LTP or LTD during a critical period and that later signals cannot interconvert these two fates.