Translational switch for long‐term maintenance of synaptic plasticity

Abstract

Memory can last a lifetime, yet synaptic contacts that contribute to the storage of memory are composed of proteins that have much shorter lifetimes. A physiological model of memory formation, long‐term potentiation (LTP), has a late protein‐synthesis‐dependent phase (L‐LTP) that can last for many hours in slices or even for days in vivo . Could the activity‐dependent synthesis of new proteins account for the persistence of L‐LTP and memory? Here, we examine the proposal that a self‐sustaining regulation of translation can form a bistable switch that can persistently regulate the on‐site synthesis of plasticity‐related proteins. We show that an αCaMKII–CPEB1 molecular pair can operate as a bistable switch. Our results imply that L‐LTP should produce an increase in the total amount of αCaMKII at potentiated synapses. This study also proposes an explanation for why the application of protein synthesis and αCaMKII inhibitors at the induction and maintenance phases of L‐LTP result in very different outcomes. ### 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 αCaMKII 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 αCaMKII). The translation of αCaMKII is controlled by another molecule, CPEB1, which is in turn controlled by αCaMKII. The structure of this molecular network is shown in [Figure 1][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. 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,][2] 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 αCaMKII. 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. 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. Mol Syst Biol. 5: 284 [1]: #F1 [2]: #F7