Protein synthesis inhibition and memory: Formation vs amnesia

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Abstract

Studies using protein synthesis inhibitors have provided key support for the prevalent view that memory formation requires the initiation of protein synthesis as a primary element of the molecular biology of memory. However, many other interpretations of the amnesia data have received far less attention. These include: (a) protein synthesis may play a constitutive role in memory formation, providing proteins prior to an experience that can be activated by training; (b) protein synthesis may be needed to replace proteins available prior to learning but ‘consumed’ by learning; (c) inhibition of protein synthesis impairs the well-being of neurons, leading to an inability to deliver resources needed for memory formation; and (d) inhibition of protein synthesis results in abnormal neural functions that interfere with memory. One of these, abnormal release of neurotransmitters after inhibition of protein synthesis, is detailed here, along with a review of many circumstances in which it appears that protein synthesis at the time of training is not required for the formation of new memories.

Evidence of activation of cell signaling molecules and transcription factors is another form of support for a role of training-initiated protein synthesis in memory. However, recent findings suggest that many of these molecules are activated by training and remain activated for days after training, i.e. activated for times well beyond those typically invoked for memory consolidation processes. Reviewing these results, this paper suggests that the long-lasting molecular changes may be the basis of a form of intracellular memory, one responsible for up-regulating the probability that a neuron, once activated in this manner, will engage in future plasticity. This view melds ideas of modulation of memory with those of consolidation of memory.

Introduction

Many reports begin with a well-accepted statement that there are at least two stages of memory. As generally proposed, memory is maintained soon after experience, by a short-lived temporary process that is dependent on modifications of existing proteins (e.g., Kandel & Schwartz, 1982). As this memory mechanism decays, mechanisms responsible for permanent memory storage supplant the temporary process. These mechanisms are generally believed to be dependent on new protein synthesis and to form the basis for cellular memory consolidation at a cellular level (Dudai, 2002, Kandel, 2001, Squire, 1987).

Of several ways in which new protein synthesis may be important to memory (Glassman, 1969), one is the commonly held view that new protein synthesis is needed for the modifications of neuron–neuron functional connectivity. Many of the studies that discuss protein synthesis-dependent memory do so on the basis of findings that protein synthesis inhibitors impair memory, identifying results obtained with the inhibitors as demonstrating a requirement for protein synthesis in memory consolidation. However, other interpretations of these findings are less often considered (Gold, 2006). One is that intact protein synthesis is necessary in a more constitutive manner for replenishment of materials used in memory formation (Routtenberg & Rekart, 2005). Another possibility is that protein synthesis is needed for maintenance of cell health at a level that can sustain the use of cellular resources to fine-tune the connectivity of the nervous system in response to memory (Rudy, Biedenkapp, Moineau, & Bolding, 2006). Yet another interpretation is that inhibition of protein synthesis results in abnormal neural functions that interfere with memory, a possibility supported by recent evidence from the author’s laboratory (Canal, Chang, & Gold, 2007) as described below.

The present paper examines several classes of findings that are not readily incorporated into the view that new protein synthesis is a necessary component of the mechanisms by which new memories are formed. Although this review will mainly focus on contemporary studies, it is important to note extensive evidence from the 1970s and 1980s that led many investigators to conclude that the evidence did not support the idea that protein synthesis was necessary for memory formation, that the effects of protein synthesis inhibitors on memory were very complex, and that the results supported many alternative explanations (e.g., Barraco and Stettner, 1976, Cooper et al., 1978, Martinez et al., 1981). These points of view were the motivation for the review by Davis and Squire (1984), in which they defended the idea that protein synthesis was necessary for memory. Importantly, whatever conclusion one now draws about this issue, it is not the case that these early studies led to a consensus that protein synthesis was necessary for memory. Nonetheless, statements espousing this view have become standard in the introductions to and rationales for studies of protein synthesis and memory.

Section snippets

Memory

Although protein synthesis inhibitors often impair memory across species and tasks, it is also the case, as noted by Routtenberg and Rekart (2005), that intact memories are sometimes formed even in the presence of extensive inhibition of protein synthesis. Specific behavioral variables appear to be important. For example, amnesia is attenuated in graded manner by increasing the number of training trials or by increasing the intertrial interval (Flood et al., 1975, Quartermain and Botwinick, 1975

If protein synthesis is not necessary for memory formation, why do inhibitors impair memory?

The many instances in which memory and synaptic plasticity can occur in the presence of inhibition of protein synthesis indicate clearly that protein synthesis is not necessary for all forms of memory and synaptic plasticity. What of the reports that do show such impairments after administration of protein synthesis inhibitors? If the examples of failures to impair memory with protein synthesis inhibitors mean that new protein synthesis is not necessary in these cases, do reports that

Proteins and protein synthesis as both modulators and substrates of memory

With considerable evidence against a general requirement for new protein synthesis in order to form new memories, additional data point to an important role for proteins, and for protein synthesis, in memory. The evidence includes training-related changes in immediate early gene expression, changes in gene microarray profiles and changes in specific proteins. One alternative to a need for new protein synthesis is that post-translational modifications of existing protein may be sufficient to

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    Research from the author’s laboratory and preparation of this manuscript supported by NIA (AG007648) and NIDA (DA016951 and DA024129).

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