title: Loss of Thr286 phosphorylation disrupts synaptic CaMKIIα targeting, NMDAR activity and behavior in pre-adolescent mice.
abstract: In order to provide insight into in vivo roles of CaMKIIα autophosphorylation at Thr286 during postnatal development, behavioral, biochemical, and electrophysiological phenotypes of pre-adolescent Thr286 to Ala CaMKIIα knock-in (T286A-KI) and WT mice were examined. T286A-KI mice displayed cognitive deficits in a novel object recognition test and an anxiolytic phenotype in the elevated plus maze, suggesting disruption of normal developmental processes. At the molecular level, the ratio of total CaMKIIα to CaMKIIβ in hippocampal lysates was significantly decreased≈2-fold in T286A-KI mice, and levels of both isoforms in synaptic subcellular fractions were decreased by≈80%. Total levels of GluA1 AMPA-glutamate receptor subunits and phosphorylation of GluA1 at the CaMKII site (Ser831) in synaptic fractions were unaltered, as were the frequency and amplitude of AMPAR-mediated spontaneous excitatory postsynaptic currents at hippocampal CA3-CA1 synapses. Synaptic levels of NMDA-glutamate receptor GluN1, GluN2A and GluN2B subunits also were unaltered. However, the reduced ratio of CaMKII to NMDAR subunits in synaptic fractions was linked to increased synaptic NMDAR-mediated currents in T286A-KI mice, apparently due to increased functional contributions by GluN2B NMDARs (assessed by Ro 25-6981 sensitivity). Thus, disruption of CaMKII synaptic targeting caused by elimination of Thr286 autophosphorylation leads to synaptic and behavioral deficits during pre-adolescence.
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Gustin
authors.forename: Brian C
authors.initials: BC
authors.lastname: Shonesy
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Robinson
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Rentz
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Baucum
authors.forename: Nidhi
authors.initials: N
authors.lastname: Jalan-Sakrikar
authors.forename: Danny G
authors.initials: DG
authors.lastname: Winder
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Stanwood
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Colbran
mesh_terms: D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D013912:Threonine / Q000378:metabolism*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D013912:Threonine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517671:Camk2a protein, mouse