GDPbS Activates Excitatory Synapses in CA1 Pyramidal Cells by Disinhibiting the PKA Activating Pathway

Abstract

Objective: During the early postnatal brain developmental stages, excitatory synapses mediated by AMPA receptors are weak or silent. Activity-dependent insertion of AMPA receptors into synapses depends on the activation of protein kinase A. In this work, we investigated the effect of Guanosine 5’-[βthiol] diphosphate (GDPsS) on excitatory and inhibitory synaptic currents in CA1 pyramidal cells at postnatal days 9-12. Methods: Whole-cell patch-clamp recordings from identified hippocampal CA1 pyramidal cells were used. GDPβS Was applied through the recording electrode. Results: GDPβS induces an increase in excitatory synaptic current amplitude, but not in the inhibitory synaptic current amplitude. An analysis of the change in excitatory synaptic current amplitude in the presence of GDPβS revealed a progressive increase, which is blocked by the protein kinase A inhibitor Rp-3’,5’-cyclic monophosphothioatetriethylamine (Rp-cAMP), suggesting that GDPβS inhibits G-protein with a tonic negative control on a protein kinase A activating pathway. In addition, GDPβS has no effect on paired-pulse facilitation, suggesting that the glutamate release machinery is not affected. Moreover, as GDPβS was applied to postsynaptic neurons, the increase in excitatory postsynaptic current amplitude is related to changes at the postsynaptic side. Conclusion: Those results suggest that in developing hippocampal CA1 pyramidal cells, the tonic inhibition of a protein kinase A activating pathway by a G-protein prevents the activation of excitatory synapses