title: Long-term potentiation-dependent spine enlargement requires synaptic Ca2+-permeable AMPA receptors recruited by CaM-kinase I.
abstract: It is well established that long-term potentiation (LTP), a paradigm for learning and memory, results in a stable enlargement of potentiated spines associated with recruitment of additional GluA1-containing AMPA receptors (AMPARs). Although regulation of the actin cytoskeleton is involved, the detailed signaling mechanisms responsible for this spine expansion are unclear. Here, we used cultured mature hippocampal neurons stimulated with a glycine-induced, synapse-specific form of chemical LTP (GI-LTP). We report that the stable structural plasticity (i.e., spine head enlargement and spine length shortening) that accompanies GI-LTP was blocked by inhibitors of NMDA receptors (NMDARs; APV) or CaM-kinase kinase (STO-609), the upstream activator of CaM-kinase I (CaMKI), as well as by transfection with dominant-negative (dn) CaMKI but not dnCaMKIV. Recruitment of GluA1 to the spine surface occurred after GI-LTP and was mimicked by transfection with constitutively active CaMKI. Spine enlargement induced by transfection of GluA1 was associated with synaptic recruitment of Ca(2+)-permeable AMPARs (CP-AMPARs) as assessed by an increase in the rectification index of miniature EPSCs (mEPSCs) and their sensitivity to IEM-1460, a selective antagonist of CP-AMPARs. Furthermore, the increase in spine size and mEPSC amplitude resulting from GI-LTP itself was blocked by IEM-1460, demonstrating involvement of CP-AMPARs. Downstream signaling effectors of CP-AMPARs, identified by suppression of their activation by IEM-1460, included the Rac/PAK/LIM-kinase pathway that regulates spine actin dynamics. Together, our results suggest that synaptic recruitment of CP-AMPARs via CaMKI may provide a mechanistic link between NMDAR activation in LTP and regulation of a signaling pathway that drives spine enlargement via actin polymerization.
authors.affiliation: Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Dale A
authors.initials: DA
authors.lastname: Fortin
authors.forename: Monika A
authors.initials: MA
authors.lastname: Davare
authors.forename: Taasin
authors.initials: T
authors.lastname: Srivastava
authors.forename: James D
authors.initials: JD
authors.lastname: Brady
authors.forename: Sean
authors.initials: S
authors.lastname: Nygaard
authors.forename: Victor A
authors.initials: VA
authors.lastname: Derkach
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Soderling
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000502:physiology*; D002413:Cations, Divalent / Q000378:metabolism; D049108:Cell Enlargement; D002463:Cell Membrane Permeability / Q000502:physiology; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology*; D013569:Synapses / Q000201:enzymology* / Q000378:metabolism
chemical_list: D002413:Cations, Divalent; D016194:Receptors, N-Methyl-D-Aspartate; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D002118:Calcium
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