Aim: 

Our main objectives were to: 1) identify PACAP receptor subtypes modulating AMPA-mediated synaptic currents in the CA1 region of rat hippocampus; 2) check for an additional action of PACAP on glutamate re-uptake; 3) check whether PACAP is locally released to modulate synaptic transmission.

Methods: 

Whole-cell membrane currents were recorded in patch-clamp from single CA1 pyramidal neurons in hippocampal slices following either stimulation of Schaffer collaterals or application of AMPA. Specific agonists or antagonists of distinct PACAP receptor subtypes were applied by an electrovalve microperfusion system.

Results: 

At a 0.5 nM dose, PACAP increased AMPA-mediated current; such effect was blocked by PACAP 6–38, a selective antagonist of PAC1 receptors, and was abolished by intracellular cAMPS-Rp, a PKA inhibitor. At 10 nM, PACAP instead reduced AMPA-mediated current; such effect was not blocked by PACAP 6–38 but was mimicked by Bay 55–9837, a selective agonist of VPAC2 receptors, and was abolished by intracellular cAMPS-Rp. Stimulation-evoked EPSCs in CA1 neurons were significantly reduced by the PAC1 antagonist PACAP 6–38, indicating that PAC1 receptors in the CA1 region are tonically activated by endogenous PACAP. Preliminary data also show that PACAP effects were modified by TBOA, an inhibitor of glutamate transporters.

Conclusion: 

Release of endogenous PACAP differentially modulates synaptic transmission by activation of PAC1 and VPAC2 receptors, both involving the cAMP/PKA pathway. In addition, PACAP affects glutamate re-uptake, which is likely to influence the AMPA/NMDA ratio of synaptic currents and modify plasticity.