Abstract

The fate of a memory, whether stored or forgotten, is determined by the ability of an active or tagged synapse to undergo changes in synaptic efficacy requiring protein synthesis of plasticity-related proteins. A synapse can be tagged, but without the "capture" of plasticity-related proteins, it will not undergo long lasting forms of plasticity (synaptic tagging and capture hypothesis). What the "tag" is and how plasticity-related proteins are captured at tagged synapses are unknown. Ca(2+)/calmodulin-dependent protein kinase II α (CaMKIIα) is critical in learning and memory and is synthesized locally in neuronal dendrites. The mechanistic (mammalian) target of rapamycin (mTOR) is a protein kinase that increases CaMKIIα protein expression; however, the mechanism and site of dendritic expression are unknown. Herein, we show that mTOR activity mediates the branch-specific expression of CaMKIIα, favoring one secondary, daughter branch over the other in a single neuron. mTOR inhibition decreased the dendritic levels of CaMKIIα protein and mRNA by shortening its poly(A) tail. Overexpression of the RNA-stabilizing protein HuD increased CaMKIIα protein levels and preserved its selective expression in one daughter branch over the other when mTOR was inhibited. Unexpectedly, deleting the third RNA recognition motif of HuD, the domain that binds the poly(A) tail, eliminated the branch-specific expression of CaMKIIα when mTOR was active. These results provide a model for one molecular mechanism that may underlie the synaptic tagging and capture hypothesis where mTOR is the tag, preventing deadenylation of CaMKIIα mRNA, whereas HuD captures and promotes its expression in a branch-specific manner.

Highlights

  • Memory requires protein synthesis of dendritic CaMKII␣

  • We have shown previously that NMDAR activity promotes the phosphorylation of mTORC1, and acute rapamycin treatment reduces it in cultured hippocampal and cortical neurons (21–28 days in vitro (DIV)) [25]

  • Because shortening of the CaMKII␣ poly(A) tail led to mRNA degradation, we examined whether the third RRM and linker region of HuD are required to mediate the HuD-dependent rescue of CaMKII␣ Branch Variability Index (BVI) when mTORC1 is inhibited

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Summary

Background

Memory requires protein synthesis of dendritic CaMKII␣. Results: HuD directs CaMKII␣ expression in a branch-specific manner. mTOR inhibition reduces HuD binding and promotes deadenylation of CaMKII␣ mRNA. Deleting the third RNA recognition motif of HuD, the domain that binds the poly(A) tail, eliminated the branch-specific expression of CaMKII␣ when mTOR was active. Model for one molecular mechanism that may underlie the synaptic tagging and capture hypothesis where mTOR is the tag, preventing deadenylation of CaMKII␣ mRNA, whereas HuD captures and promotes its expression in a branch-specific manner. Our findings provide a model in which mTORC1 activity and the branch-specific targeting of HuD determine which mRNAs are available to be translated and in turn the propensity of a dendritic branch to undergo site-specific and long lasting forms of plasticity

Experimental Procedures
Results
F Vehicle
D Branch Variability Index
Discussion
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