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Presynaptic Mechanism Underlying cAMP-Induced Synaptic Potentiation in Medial Prefrontal Cortex Pyramidal Neurons

Department of Pharmacology, College of Medicine, and Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan, Taiwan

cAMP, a classic second messenger, has been proposed recently to participate in regulating prefrontal cortical cognitive functions, yet little is known about how it does so. In this study, we used forskolin, an adenylyl cyclase activator, to examine the effects of cAMP on excitatory synaptic transmission in the medial prefrontal cortex (mPFC) using whole-cell patch-clamp recordings from visually identified layer II-III or V pyramidal cells in vitro. We found that bath application of forskolin significantly increased the amplitude of excitatory postsynaptic currents (EPSCs) in a concentration- and age-dependent manner. This enhancement was completely abolished by coapplication of cAMP-dependent protein kinase (PKA) inhibitor and p42/p44 mitogen-activated protein kinase (MAPK) kinase inhibitor, but not application of either drug alone. The membrane-permeable cAMP analog adenosine 3',5'-cyclic monophosphorothioate, Sp-isomer, triethylammonium salt, or activation of -adrenergic receptor by isoproterenol mimicked the effect of forskolin to potentiate EPSCs. However, neither exchange protein activated by cAMP (Epac) inhibitor brefeldin A nor hyperpolarization and cyclic nucleotide-activated channel blocker 4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride (ZD7288) affected forskolin response. The augmentation of EPSCs by forskolin was accompanied by a reduction of the synaptic failure rate, coefficient of variation and paired-pulse ratio of EPSCs, and an increase in release probability and number of releasable synaptic vesicles. Forskolin also significantly increased the frequency of miniature EPSCs without altering their amplitude distribution. These results indicate that cAMP acts presynaptically to elicit a synaptic potentiation on the layer V pyramidal neurons of mPFC through converging activation of PKA and p42/p44 MAPK signaling pathways.

Address correspondence to: Dr. Kuei-Sen Hsu, Department of Pharmacology, College of Medicine, National Cheng Kung University, 1, University Rd., Tainan City 701, Taiwan. E-mail:richard{at}mail.ncku.edu.tw

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