Altered protein synthesis is a trigger for long-term memory formation

Abstract

There is ongoing debate concerning whether new protein synthesis is necessary for, or even contributes to, memory formation and storage. This review summarizes a contemporary model proposing a role for altered protein synthesis in memory formation and its subsequent stabilization. One defining aspect of the model is that altered protein synthesis serves as a trigger for memory consolidation. Thus, we propose that specific alterations in the pattern of neuronal protein translation serve as an initial event in long-term memory formation. These specific alterations in protein readout result in the formation of a protein complex that then serves as a nidus for subsequent perpetuating reinforcement by a positive feedback mechanism. The model proposes this scenario as a minimal but requisite component for long-term memory formation. Our description specifies three aspects of prevailing scenarios for the role of altered protein synthesis in memory that we feel will help clarify what, precisely, is typically proposed as the role for protein translation in memory formation. First, that a relatively short initial time window exists wherein specific alterations in the pattern of proteins translated (not overall protein synthesis) is involved in initializing the engram. Second, that a self-perpetuating positive feedback mechanism maintains the altered pattern of protein expression (synthesis or recruitment) locally. Third, that other than the formation and subsequent perpetuation of the unique initializing proteins, ongoing constitutive protein synthesis is all that is minimally necessary for formation and maintenance of the engram. We feel that a clear delineation of these three principles will assist in interpreting the available experimental data, and propose that the available data are consistent with a role for protein synthesis in memory.

Figure 1

A minimal model for protein synthesis as a trigger for long-term memory formation. The model summarized in this figure makes a large number of assumptions for simplicity’s sake: that these events occur locally at a dendritic spine, and that the process is NMDA receptor-dependent. The model does not specify molecules or mechanisms, and it ignores the need for altered gene expression. In this model a memory-causing event such as a set of appropriately contingent environmental signals leads to NMDA receptor activation and the subsequent formation of a memory engram. NMDA receptor activation recruits signal transduction mechanisms to precipitate an altered rate of synthesis of a subset of synaptic proteins. This altered protein synthesis is in addition to “housekeeping” protein synthesis that contributes to ongoing maintenance of the dendritic spine (blue pathway). Also, the spine maintains constitutive synthesis of effector proteins that when complexed with the appropriate partners can increase synaptic strength (the green pathway). The targets of the signal for altered protein synthesis (the red pathway) comprise the appropriate partners for the green pathway, in order to increase synaptic strength. Thus, the altered synthesis of the appropriate proteins is the trigger for synaptic potentiation, and the “new” proteins interact with other proteins already present to effect the change. The effector protein complex is the readout of the altered protein synthesis. The red pathway becomes quasi-constitutive by a positive feedback mechanism. Thus, the triggering mechanism can perpetuate itself by one of two possible mechanisms. First, it might promote its own re-synthesis at a new higher rate locally in order to perpetuate the altered spectrum (or rate) of synthesis of a subset of local effector proteins. This mechanism is what is illustrated in this figure. Alternatively and minimally, the complex might perpetuate itself by an increased rate of recruitment to the locale of a protein synthesized globally throughout the cell. One of these two mechanisms is the maintenance mechanism at the molecular level. The self-perpetuating structural/functional change is a component of the engram, and serves as a molecular basis for memory storage.

Figure 2

The four basic kinds of experiments to examine the role of altered protein synthesis in memory formation. A hypothesis leads to four fundamental types of predictions (predicted observations or predicted experimental outcomes). In this table, or each category of experiment, both the general form of the predictions (left-hand column) and the specific predictions of the hypothesis that altered protein synthesis is involved in memory (right-hand column), are shown. See text for additional discussion.

Figure 3

Signaling pathways controlling protein synthesis in neurons.