On the mechanism of synaptic depression induced by CaMKIIN, an endogenous inhibitor of CaMKII

• Published in: PloS one Vol. 7; no. 11; p. e49293
• Main Authors: Gouet, Camilo, Aburto, Belen, Vergara, Cecilia, Sanhueza, Magdalena
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08-11-2012; Public Library of Science (PLoS)
• Subjects: Animals; Biology; Brain; Brain slice preparation; Ca2+/calmodulin-dependent protein kinase II; Calcium binding proteins; Calcium Signaling - physiology; Calcium signalling; Calcium-binding protein; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - analysis; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Calmodulin; Carrier Proteins - metabolism; Carrier Proteins - physiology; Cerebral blood flow; Dendritic spines; Glutamatergic transmission; Glutamic acid receptors (ionotropic); Hippocampus; Hippocampus - metabolism; Homeostatic plasticity; Inhibitors; Ischemia; Kinases; Learning; Long-term depression; Long-Term Potentiation; Long-Term Synaptic Depression; Medical screening; Memory; Metabolic pathways; N-Methyl-D-aspartic acid receptors; Occlusion; Peptides; Phosphorylation; Plasticity; Postsynaptic density; Proteasomes; Protein biosynthesis; Protein kinases; Protein synthesis; Protein Transport; Proteins; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - metabolism; Receptors, N-Methyl-D-Aspartate - physiology; Regulators; RNA, Messenger - metabolism; Saturation; Synapses; Synaptic depression; Synaptic plasticity; Synaptic strength; Chile
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0049293

Activity-dependent synaptic plasticity underlies, at least in part, learning and memory processes. NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) is a major synaptic plasticity model. During LTP induction, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated, autophosphorylated and persistently translocated to the postsynaptic density, where it binds to the NMDAR. If any of these steps is inhibited, LTP is disrupted. The endogenous CaMKII inhibitor proteins CaMKIINα,β are rapidly upregulated in specific brain regions after learning. We recently showed that transient application of peptides derived from CaMKIINα (CN peptides) persistently depresses synaptic strength and reverses LTP saturation, as it allows further LTP induction in previously saturated pathways. The treatment disrupts basal CaMKII-NMDAR interaction and decreases bound CaMKII fraction in spines. To unravel CaMKIIN function and to further understand CaMKII role in synaptic strength maintenance, here we more deeply investigated the mechanism of synaptic depression induced by CN peptides (CN-depression) in rat hippocampal slices. We showed that CN-depression does not require glutamatergic synaptic activity or Ca(2+) signaling, thus discarding unspecific triggering of activity-dependent long-term depression (LTD) in slices. Moreover, occlusion experiments revealed that CN-depression and NMDAR-LTD have different expression mechanisms. We showed that CN-depression does not involve complex metabolic pathways including protein synthesis or proteasome-mediated degradation. Remarkably, CN-depression cannot be resolved in neonate rats, for which CaMKII is mostly cytosolic and virtually absent at the postsynaptic densities. Overall, our results support a direct effect of CN peptides on synaptic CaMKII-NMDAR binding and suggest that CaMKIINα,β could be critical plasticity-related proteins that may operate as cell-wide homeostatic regulators preventing saturation of LTP mechanisms or may selectively erase LTP-induced traces in specific groups of synapses.