Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation.
Local protein translation in dendrites could be a means for delivering synaptic proteins to their sites of action, perhaps in a spatially regulated fashion that could contribute to plasticity. To directly test the functional role of dendritic translation of calcium/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) in vivo, we mutated the endogenous gene to disrupt the dendritic localization signal in the mRNA. In this mutant mouse, the protein-coding region of CaMKIIalpha is intact, but mRNA is restricted to the soma. Removal of dendritic mRNA produced a dramatic reduction of CaMKIIalpha in postsynaptic densities (PSDs), a reduction in late-phase long-term potentiation (LTP), and impairments in spatial memory, associative fear conditioning, and object recognition memory. These results demonstrate that local translation is important for synaptic delivery of the kinase and that local translation contributes to synaptic and behavioral plasticity.
Miller
Stephan
S
Department of Cell Biology and Institute for Childhood and Neglected Diseases, The Scripps Research Institute, 10550 North Torrey Pines Road, ICND 202, La Jolla, CA 92037, USA. stephanm@scripps.edu
Yasuda
Masahiro
M
Coats
Jennifer K
JK
Jones
Ying
Y
Martone
Maryann E
ME
Mayford
Mark
M
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000172:deficiency* / Q000235:genetics; D002678:Chimera; D003712:Dendrites / Q000201:enzymology*; D005239:Fear / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D018390:Gene Targeting; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology* / Q000254:growth & development*; D017774:Long-Term Potentiation / Q000235:genetics*; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009924:Organ Culture Techniques; D010641:Phenotype; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics*
D020033:Protein Isoforms; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517671:Camk2a protein, mouse