Requirement for protein synthesis at developing synapses.
Activity and protein synthesis act cooperatively to generate persistent changes in synaptic responses. This forms the basis for enduring memory in adults. Activity also shapes neural circuits developmentally, but whether protein synthesis plays a congruent function in this process is poorly understood. Here, we show that brief periods of global or local protein synthesis inhibition decrease the synaptic vesicles available for fusion and increase synapse elimination. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a critical target; its levels are controlled by rapid turnover, and blocking its activity or knocking it down recapitulates the effects of protein synthesis inhibition. Mature presynaptic terminals show decreased sensitivity to protein synthesis inhibition, and resistance coincides with a developmental switch in regulation from CaMKII to PKA (protein kinase A). These findings demonstrate a novel mechanism regulating presynaptic activity and synapse elimination during development, and suggest that protein translation acts coordinately with activity to selectively stabilize appropriate synaptic interactions.
Sebeo
Joseph
J
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA .
Hsiao
Kuangfu
K
Bozdagi
Ozlem
O
Dumitriu
Dani
D
Ge
Yongchao
Y
Zhou
Qiang
Q
Benson
Deanna L
DL
D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008959:Models, Neurological; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D013572:Synaptic Vesicles / Q000187:drug effects* / Q000502:physiology*
D054758:A Kinase Anchor Proteins; D011500:Protein Synthesis Inhibitors; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2