Translational switch for long-term maintenance of synaptic plasticity

Naveed Aslam¹, Yoshi Kubota¹, David Wells² & Harel Z Shouval^1,3

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Synopsis

Each of us has memories that we can remember throughout our lifetime. Such memories are encoded, at the cellular level, by changes of synaptic efficacies. At the molecular level, changes in synaptic efficacies are expressed by changes in the number or conformational states of synaptic proteins. Synaptic proteins, however, have a much shorter lifetime than memories. How are such memories maintained despite a fast turnover of their molecular substrate? One clue is that the maintenance of long-term memories requires the synthesis of new proteins. It is therefore feasible that the synthesis of new proteins compensates for the limited lifetimes of synaptic proteins. For such protein synthesis to be a mechanism for the maintenance of memory, it has to occur only in some synapses within one cell and not in others. Such synapse-specific control of protein synthesis is unlikely to be implemented at the level of transcription. Experimental results have shown that the machinery for the translation of new proteins can be found in the vicinity of synapses, mRNAs for key synaptic proteins are found in synapses, and that translation of such proteins can be locally activated and can be regulated by translation factor proteins. Therefore, the regulation of translation might be a mechanism for synapse-specific, protein-synthesis-dependent long-term memory.

Here, we propose that a self-sustaining, synapse-specific translational switch can account for the maintenance of memory despite protein turnover. This switch is based on a positive feedback loop between a memory protein and a translation factor protein, which regulates the synthesis of the memory protein through a closed loop. We select CaMKII as a specific instantiation of the regulated molecule because of its functional interactions as well as its relative abundance (almost 2% of total protein in brain is CaMKII). The translation of CaMKII is controlled by another molecule, CPEB1, which is in turn controlled by CaMKII. The structure of this molecular network is shown in Figure 1. We test the feasibility of this idea by implementing a mathematical mass-action model of this molecular network. We show that our proposed molecular network can indeed be a bistable switch. The 'up' state of this switch represents activity-induced memory formation and the 'down' state represents the basal synaptic conductance.

Figure 1

The proposed model of the local CaMKII synthesis through the CaMKII–CPEB1 molecular loop. Here, the CaMKII molecule can be in inactive, active or active and phosphorylated state, whereas CPEB1 can be in unphosphorylated or phosphorylated state. The CaMKII molecule in each of the three states has a finite turnover time. A new CaMKII molecule is produced by CPEB1-dependent polyadenylation of CaMKII mRNA, which is represented by translation stage (T).

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Previous experimental results have shown that protein synthesis inhibitors can prevent the formation of new memories but cannot cause us to forget memories that have been consolidated. These results could be interpreted as an indication that protein synthesis has no role in memory maintenance, posing a fundamental challenge to our hypothesis. Using our mathematical model, we show that the requirements for protein synthesis are very different during the formation of a new memory and during the maintenance of existing memory. In Figure 7, we show the differential effect of a partial blocking of protein synthesis during the induction and maintenance phases of memory formation. During the induction phase, a short moderate block of protein synthesis is sufficient for preventing the formation of a new memory, whereas during the maintenance phase, much longer and more complete blocks are required to reverse a previously established memory. Similar results are obtained with activity blockers of CaMKII. These results suggest new experiments in which the duration and effectiveness of protein synthesis and activity blockers are taken into account. Such experiments can test the validity of this theory.

Figure 7

Blocking of protein synthesis in early and late phases. Simulations are implemented with and without a (Ca²⁺)₄–CaM pulse. The solid line indicates the CaMKII concentration without any pulse stimulus, whereas the dotted line indicates the CaMKII concentration with pulse stimulus (pulse stimulus is used to mimic the effect of HFS). (A) Protein synthesis blocking during induction for 33 min (solid thick black line shows blocking time). For different levels of blocking, L-LTP has a different outcome during the maintenance phase. (B) Protein synthesis blocking during maintenance for 1300 min (the solid thick black line shows blocking time). Even for high-percentage blocking, the upregulated state can still be maintained, suggesting that if CaMKII is a trace for L-LTP, its expression can still be observed, even if synthesis of new proteins is blocked.

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Memory cannot be understood solely at the molecular level, and a complete understanding of memory formation and maintenance needs to take into account the different brain structures involved and the neuronal networks within each of these brain structures. However, all such higher level theories must be based on a solid understanding of what occurs at the molecular level. The theory proposed here suggests a molecular-level mechanism on which the maintenance of memory at the neuronal network level might be based.

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