cGMP-induced presynaptic depression and postsynaptic facilitation at glutamatergic synapses in visual cortex.
The mechanisms by which the intracellular messenger cGMP can modulate synaptic efficacy remain poorly understood. Here we report that cGMP, acting through cGMP-dependent protein kinase (PKG), has multiple rapid and reversible effects on synaptic transmission in slices and cultures of rodent visual cortex. Extracellular application of the membrane permeable cGMP analog 8-bromoguanosine-3',5'-cyclic monophosphate (8-Br-cGMP) and the PKG specific activator beta-phenyl-1,N2-etheno-8-bromoguanosine-3',5'-cyclic monophosphorothioate sp-isomer (Sp-8-Br-PET-cGMPS) reduced stimulus-evoked EPSPs in slices. In cortical cultures, both analogs reduced the frequency of spontaneous EPSCs, but not their amplitude. In both slices and cultures, intracellular perfusion of the postsynaptic neurons with a pseudosubstrate inhibitory peptide specific for PKG had no effect on the reduction in EPSPs and EPSCs, indicating that the inhibition occurred at presynaptic sites. Whole-cell calcium currents in cultured cortical neurons were also reduced by both analogs, which may account for the effect on synaptic release. To determine whether cGMP was also acting at postsynaptic sites, we applied exogenous kainate/AMPA and NMDA to the recorded cells directly. cGMP and its analogs showed little effect on the postsynaptic kainate/AMPA responses but produced a dramatic enhancement of NMDA responses. cGMP-induced NMDA potentiation was prevented by the specific PKG inhibitory peptide infused into the postsynaptic cell. In summary, cGMP, acting through PKG, had depressive presynaptic and facilitatory postsynaptic actions at excitatory synapses in the visual cortex. We suggest that these opposing actions may be useful for altering the balance of synaptic inputs to cortical neurons in ways that enhance signals important for synaptic facilitation and neuronal plasticity.
Wei
Ji Ye
JY
Department of Ophthalmology and Visual Science, Yale University School of Medicine, 330 Cedar Street, P.O. Box 208061, New Haven, CT 06520-8061, USA.
Jin
Xiaotao
X
Cohen
Ethan D
ED
Daw
Nigel W
NW
Barnstable
Colin J
CJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D018698:Glutamic Acid / Q000502:physiology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000502:physiology*; D051381:Rats; D014793:Visual Cortex / Q000166:cytology / Q000502:physiology*
C104224:8-bromo-beta-phenylethenoguanosine 3',5'-cyclic monophosphate; D015220:Calcium Channels; D018690:Excitatory Amino Acid Agonists; D009842:Oligopeptides; C016276:8-bromocyclic GMP; D018698:Glutamic Acid; D016202:N-Methylaspartate; C088028:arginyl-lysyl-arginyl-alanyl-arginyl-lysyl-glutamic acid; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D002118:Calcium