The de novo protein synthesis theory of memory formation is a hypothesis about the formation of the physical correlates of memory in the brain. It is widely accepted that the physiological correlates for memories are stored at the synapse between various neurons. The relative strength of various synapses in a network of neurons form the memory trace, or ‘engram,’ though the processes that support this finding are less thoroughly understood. The de novo protein synthesis theory states that the production of proteins is required to initiate and potentially maintain these plastic changes within the brain. It has much support within the neuroscience community, but some critics claim that memories can be made independent of protein synthesis.
History
Originally, protein synthesis inhibitors (PSI) were only used as antibiotics. Through various mechanisms unique to each PSI, they would inhibit the synthesis of proteins, generally at the translational level. They achieved renown within the biological scientific community, when research on protein synthesis required PSI's to investigate certain physiological processes. Through this line of research, it was found that injection of PSI in the hippocampus resulted in amnesia: the memories undergoing consolidation at the time of injection were lost (Flexner & Flexner, 1966). After the injection, the animals (generally rats) would have their memories retested, and, as a consequence of interrupted memory consolidation, they reacted to a familiar situation as though they were in a novel environment. This gave rise to the de novo protein synthesis theory: the formation of a long-term memory requires the synthesis of new proteins.
Eric Kandel established many of the biochemical markers of learning and memory in the Aplysia (California sea slug) in the 1970s, as his findings suggested potential pathways surrounding protein synthesis (Abel, Nguyen, Barad, Deuel, Kandel & Bourtchouladze, 1997). He won the Nobel prize in 2000 for his research (Kandel, n.d.). In the same year, Nader published his findings about the liability of retrieved memories that had already undergone consolidation. (Nader, Schafe, & Le Doux, 2000). For example, memories of past events are examples of memories that have already been consolidated. Nader discovered that, in the process of remembering, retrieved memories that became reactivated would require consolidation again. Various factors could interrupt this process; but without protein synthesis, memory re-consolidation would not occur and would result in the potential loss of the retrieved memory. This has been known as the reconsolidation theory of memory, which states that, after reactivation, memories undergo a process similar to initial consolidation to return them to their permanent state. Since then, a wealth of research has been done to clarify the mechanisms, genes, and proteins involved in the physiological correlate of memory.
Protein synthesis inhibitors
Protein synthesis inhibitors are a class of antibiotics, which prevent the production of new proteins by inhibiting the cell's gene expression ("Protein synthesis inhibitors", PSI). They generally operate at the ribosomal level through various mechanisms that prevent the ribosome from completing translation (Vazquez, 1967). Protein synthesis inhibitors that work in prokaryotic cells are often used as clinically prescribed antibiotics, while those that act of eukaryotic cells have been adapted for research purposes. In research, commonly used PSI's include anisomycin, cycloheximide, and puromycin - although the use of puromycin has stopped recently because of its toxic qualities and numerous side effects (Burka, Ballas, & Sabesin, 1975). Anisomycin has relatively high effectiveness in inhibiting protein synthesis and has a large effective time window (Villers, Godaux, & Ris, 2012). Cycloheximide is frequently used in acute studies, because of its high level of inhibition and ease of reversibility (Villers, Godaux, & Ris, 2012).