Alpha-synuclein involvement in hippocampal synaptic plasticity: role of NO, cGMP, cGK and CaMKII.
Synaptic plasticity involves a series of coordinate changes occurring both pre- and postsynaptically, of which alpha-synuclein is an integral part. We have investigated on mouse primary hippocampal neurons in culture whether redistribution of alpha-synuclein during plasticity involves retrograde signaling activation through nitric oxide (NO), cGMP, cGMP-dependent protein kinase (cGK) and calmodulin-dependent protein kinase II. We have found that deletion of the alpha-synuclein gene blocks both the long-lasting enhancement of evoked and miniature transmitter release and the increase in the number of functional presynaptic boutons evoked through the NO donor, DEA/NO, and the cGMP analog, 8-Br-cGMP. In agreement with these findings both DEA/NO and 8-Br-cGMP were capable of producing a long-lasting increase in number of clusters for alpha-synuclein through activation of soluble guanylyl cyclase, cGK and calcium/calmodulin-dependent protein kinase IIalpha. Thus, our results suggest that NO, cGMP, GMP-dependent protein kinase and calmodulin-dependent protein kinase II play a key role in the redistribution of alpha-synuclein during plasticity.
Liu
Shumin
S
Department of Pathology, Taub Institute, Columbia University, New York, NY 10032, USA.
Fa
Mauro
M
Ninan
Ipe
I
Trinchese
Fabrizio
F
Dauer
William
W
Arancio
Ottavio
O
D000818:Animals; D000831:Animals, Newborn; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002452:Cell Count; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D051844:alpha-Synuclein / Q000172:deficiency / Q000378:metabolism*
D004791:Enzyme Inhibitors; D051844:alpha-Synuclein; D009569:Nitric Oxide; D018698:Glutamic Acid; D017869:Cyclic GMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517671:Camk2a protein, mouse; D006152:Cyclic GMP