The role of protein synthesis in memory consolidation: Progress amid decades of debate

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Abstract

A major component of consolidation theory holds that protein synthesis is required to produce the synaptic modification needed for long-term memory storage. Protein synthesis inhibitors have played a pivotal role in the development of this theory. However, these commonly used drugs have unintended effects that have prompted some to reevaluate the role of protein synthesis in memory consolidation. Here we review the role of protein synthesis in memory formation as proposed by consolidation theory calling special attention to the controversy involving the non-specific effects of a group of protein synthesis inhibitors commonly used to study memory formation in vivo. We argue that molecular and genetic approaches that were subsequently applied to the problem of memory formation confirm the results of less selective pharmacological studies. Thus, to a certain extent, the debate over the role of protein synthesis in memory based on interpretational difficulties inherent to the use of protein synthesis inhibitors may be somewhat moot. We conclude by presenting avenues of research we believe will best provide answers to both long-standing and more recent questions facing field of learning and memory.

Introduction

I sometimes feel, in reviewing the evidence on the localization of the memory trace, that the necessary conclusion is that learning is just not possible (Lashley, 1950).

One of the most puzzling questions facing psychologists and neurobiologists alike is one that was posed centuries ago: what is the nature of memory? How does wakeful experience alter neural circuits within the brain in such a precise and meaningful way that even decades later we are able to invoke a remarkably detailed percept of our own history? Indeed, the formation of cognitive associations between external stimuli or between our actions and their consequences can be demonstrated with relative ease. However, it is considerably more difficult to causally connect cellular and molecular events to the instantiation of such associations. Nevertheless, we are now equipped with sophisticated molecular and genetic techniques that afford us the opportunity to probe deeper than ever before into the molecular underpinnings of memory.

In the first section of this review, we examine the emergence of consolidation theory—the idea that memories are stabilized over time—recalling several important findings that were seminal to its development and continuing evolution. We then examine the basis of the long-standing debate regarding the validity of a major tenet of consolidation theory: that new proteins must be synthesized to stabilize newly acquired memories. Indeed, this debate, although ignored by many, has never been resolved to the satisfaction of some. We then briefly summarize the remarkable progress that has been made in understanding consolidation in spite of this debate and present promising new approaches being developed to address some old questions as well as questions that have arisen along the way. Lastly, we conclude by addressing a few alternatives or addendums to consolidation theory that merit consideration.

Section snippets

The emergence of consolidation theory: The role of studies using protein synthesis inhibitors

Early empirical forays investigating memory function began in 1878 when Hermann Ebbinghaus introduced the concept of “retroactive interference”. Using sequentially memorized lists of nonsense syllables, Ebbinghaus showed that “forgetting” could be attributed to the interfering effects of subsequently learned matter (Ebbinghaus, 1885), thereby establishing the existence of temporal constraints on memory formation and storage. In 1900, using improved methodology and controls, Müller and Pilzecker

Putting the breaks on translation: Non-specific effects of protein synthesis inhibitors on memory

By providing the first experimental evidence of a protein synthesis-dependent stage of memory formation, the Flexners catalyzed the incorporation of protein synthesis into the very definition of consolidation. Ironically, it was also the Flexners who incited the ongoing debate regarding the actual role of de novo protein synthesis in memory formation. Adding to the irony is that this theoretical “about face” was sparked after Flexner and colleagues demonstrated that an injection of saline could

Synaptic plasticity, long-term memory and protein synthesis: Progress amid the debate

Before we entertain this question, it is important to describe some of the advances the field has achieved since the 1960s and 1970s. The early pharmacological experiments with inhibitors of protein synthesis captured the interest of biochemists and molecular and cellular biologists, providing the inspiration to tackle complex behavioral phenomena including learning and memory. Indeed, a wide range of significant insights into memory storage have since been gained (Kandel, 2001). These cellular

The changing role of protein synthesis in consolidation theory

The past few decades of research have shed light on activity-dependent processes that lead to changes in gene expression and the subsequent induction of protein synthesis in the soma. However, it is unclear how such changes are able to alter the strength of particular synaptic connections within a neuron. Returning to our previous question: could it be that de novo protein synthesis is not the main mechanism by which memories are permanently stabilized? Recent data suggests that the nucleus is

New approaches in the investigation of protein synthesis in memory formation

The inadequacies of protein synthesis inhibitors still in common use must be overcome and new methods that target translation must be developed. Indeed, the challenge we currently face in terms understanding learning-related protein synthesis is to demonstrate that which is induced not what is needed for general housekeeping functions. Here we summarize how targeted disruption of translation through genetic and pharmaco-genetic approaches has recently been employed to explore the role of

Post-translational modification of synaptic proteins in memory formation

In light of interpretational difficulties regarding the effects protein synthesis inhibitors on memory (and a lack of pharmacological agents that are able to specifically inhibit protein synthesis), Routtenberg and Rekart have proposed a provocative, less “translation-centric” model of memory formation centering, instead, on the function of post-translational modifications (PTMs) to the local milieu of pre-existing synaptic proteins (Routtenberg & Rekart, 2005).

At its core, PTM theory, at least

Final thoughts

It would be difficult to identify a scientific field that has benefited so dramatically from the contributions of such numerous and diverse methodologies as has the study of learning and memory. Approaches deriving from behavior, electrophysiology, pharmacology, genetics and molecular and cellular biology have been indispensable tools in unlocking the riddles of memory formation. Although there may not be agreement on the nature of the molecular mechanisms underlying amnesia induced by protein

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