The Persistence Of Memory

The great mystery of memory is how it endures. The typical neural protein only lasts for a few weeks, the cortex in a constant state of reincarnation. How, then, do our memories persist? It’s as if our remembered past can outlast the brain itself.

But wait: the mystery gets even more mysterious. A neuronal memory cannot simply be strong: it must also be specific. While each neuron has only a single nucleus, it has a teeming mass of dendritic branches. These twigs wander off in every direction, connecting to other neurons at dendritic synapses (imagine two trees whose branches touch in a dense forest). It is at these tiny crossings that our memories are made: not in the trunk of the neuronal tree, but in its sprawling canopy.

This means that every memory – represented as an altered connection between cells – cannot simply endure. It must endure in an incredibly precise way, so that the wiring diagram remains intact even as the mind gets remade, those proteins continually recycled.

The paradox of long-term memory has led neuroscientists to search for a so-called synaptic marker, a protein that would mark a particular synapse as a long-term memory and thus allow that synapse to maintain its strengthened connection for years at a time. As a result, Proust could remember his madeleine and I can recall that delicious Baskin Robbins ice cream cake, served at my 8th birthday party.

A new paper in Cell provides a fascinating glimpse into how this marking process might happen. According to research led by Kausik Si at the Stowers Institute in Kansas City, it appears that one of the essential regulators of long-term memory – an ingredient that provides both persistence and specificity – is a protein called CPEB, or cytoplasmic polyadenylation element-binding protein.

In his latest paper, Si and colleagues have shown that this awkwardly named neural protein has a rather special quality, in that forms oligomers, or self-copying clusters. (In essence, the protein can cut and paste itself over and over again, like a biological version of command-V.) Interestingly, these oligomers are incredibly sturdy, proving resistant to all the usual lab solvents. While most proteins are easily unraveled, these repeating knots of CPEB can survive even the harshest environments. Furthermore, they also seem able to actively sustain themselves, serving as templates for the formation of new oligomers in the vicinity. It’s as if they’re infectious.

While Si has previously studied CPEB in sea slugs (Aplysia) and yeast, he’s now moved on to fruit flies, looking at an insect version of the CPEB protein known as Orb2. Like its counterpart in Aplysia, Orb2 also forms oligomers within neurons. Furthermore, by selectively disrupting the ability of Orb2 to copy itself, the scientists were able to show that this copying process (and not the concentration of Orb2 in neurons) was the key to forming long-term memories. Although the mutant flies could maintain a memory for twenty-four hours, they were unable to remember anything beyond that time frame; the past did not persist.

This research builds on a decade of work, largely by Si, showing the importance of CPEB for the maintenance of long-term memories. Si’s most controversial claim has to do with the sturdiness of the protein, or why it can endure while every other neural protein experiences such rapid turnover. His first clue came largely by accident, as he was decoding the protein’s amino acid sequence. Most proteins read like a random list of letters, their structures a healthy mix of different amino acids. CPEB, however, looked quite peculiar. One end of the protein had a weird series of amino acid repetitions, as if its DNA had had a stuttering fit (Q stands for the amino acid Glutamine): QQQLQQQQQQBQLQQQQ

Immediately, Si began looking for other molecules with similarly odd repetitions. In the process, he stumbled into one of the most controversial areas of biology: He found what looks like a prion. Prions were once regarded as the nasty pathogen for a tribe of the worst diseases on earth: Mad-cow disease, fatal familial insomnia (where you stop being able to fall asleep and after three months die of insomnia) and a host of other neuro-degenerative diseases.

Prions are still guilty of causing these horrific deaths. In recent years, however, it’s become clear that proteins with prion-like properties might play an important biological role in healthy tissue. First, a definition: Prions are roughly defined as a class of proteins that can exist in two functionally distinct states (every other protein has only one natural state). One of these states is “active” and one is “inactive”. Furthermore, Prions can switch states (turning themselves on) without any guidance from above; they can change their proteomic structure without undergoing any genetic changes. And once a prion is turned on, it can transmit its new, infectious structure to neighboring cells with no actual transfer of genetic material.

In other words, prions violate most of biology’s sacred rules. They are one of those annoying reminders of how much we don’t know. (It’s important, I think, to not get too caught up for now in the nomenclature. CPEB might not be a prion in the most literal sense, but it certainly has properties that are prion-esque.) In fact, prion-like proteins in neurons may provide an important key to understanding the mysterious endurance of memory. Take CPEB, this synaptic ingredient that can copy itself, with additional copies serving as an indicator of synaptic strength. Like a prion, this “active” version of CPEB is virtually indestructible. It’s also “infectious,” able to recruit single copies of the protein to join its cut-and-pasting party. Lastly, CPEB seems to be regulated by neural stimulation, so that training fruit flies with a simple learning paradigm triggers the start of the oligomerization, or copying, process. The protein has been flicked on; the synapse has been marked as a memory.

What’s astonishing, of course, is that no further action is required. Thanks to the strange properties of CPEB, this tangle can last as long as we do, suriving the withering acids of time. Perhaps we remember because this protein cannot be undone.

Full disclosure: I worked with Dr. Si in the Kandel lab several years ago. He remains a friend.