Scientists Create Novel Approach to Find RNAs Involved in Long-term Memory Storage

Despite decades of research, relatively little is known about the identity of RNA molecules that are transported as part of the molecular process underpinning learning and memory.

Now, working together, scientists from the Florida campus of The Scripps Research Institute (TSRI), Columbia University and the University of Florida, Gainesville, have developed a novel strategy for isolating and characterizing a substantial number of RNAs transported from the cell-body of neuron (nerve cell) to the synapse, the small gap separating neurons that enables cell to cell communication.

Using this new method, the scientists were able to identify nearly 6,000 transcripts (RNA sequences) from the genome of Aplysia, a sea slug widely used in scientific investigation.

The scientists’ target is known as the synaptic transcriptome—roughly the complete set of RNA molecules transported from the neuronal cell body to the synapse.

In the study, published recently in the journal Proceedings of the National Academy of Sciences, the scientists focused on the RNA transport complexes that interact with the molecular motor kinesin; kinesin proteins move along filaments known as microtubules in the cell and carry various gene products during the early stage of memory storage.

While neurons use active transport mechanisms such as kinesin to deliver RNA cargos to synapses, once they arrive at their synaptic destination that service stops and is taken over by other, more localized mechanisms—in much the same way that a traveler’s bags gets handed off to the hotel doorman once the taxi has dropped them at the entrance.

The scientists identified thousands of these unique sequences of both coding and noncoding RNAs. As it turned out, several of these RNAs play key roles in the maintenance of synaptic function and growth.

The scientists also uncovered several antisense RNAs (paired duplicates that can inhibit gene expression), although what their function at the synapse might be remains unknown.

“Our analyses suggest that the transported RNAs are surprisingly diverse,” said Sathya Puthanveettil, a TSRI assistant professor who designed the study. “It also brings up an important question of why so many different RNAs are transported to synapses. One reason may be that they are stored there to be used later to help maintain long-term memories.”

The team’s new approach offers the advantage of avoiding the dissection of neuronal processes to identify synaptically localized RNAs by focusing on transport complexes instead, Puthanveettil said. This new approach should help in better understanding changes in localized RNAs and their role in local translation as molecular substrates, not only in memory storage, but also in a variety of other physiological conditions, including development.

“New protein synthesis is a prerequisite for maintaining long term memory,” he said, “but you don’t need this kind of transport forever, so it raises many questions that we want to answer. What molecules need to be synthesized to maintain memory? How long is this collection of RNAs stored? What localized mechanisms come into play for memory maintenance? ”

Memory Molecules

link to the page in question here -> http://ca.io9.com/5796702/our-most-traumatic-memories-could-be-erased-thanks-to-the-marine-snail

Link to asker here -> Superfoo

Ah yes. This is most fascinating! We were studying the molecular mechanisms behind memory last semester, and funnily enough, it is one of things that has really stuck with me. 

Simply put, memory can be reduced to changes in the way neurons fire impulses. Memory is a change in the nervous system, in response to an experience or stimulus. Memory formation is a vastly complicated process which relies on multiple mechanisms, but the best elucidated one is the one known as Long Term Potentiation, which I’ll attempt to explain simply. 

Just say we have 2 neurons in series. Neuron A is releasing neurotransmitter into the synapse to act on neuron B, to tell it to fire. If Neuron A is more stimulated than usual (as a result of somekind of experience), then neuron A will release more neurotransmitter into the synapse. More neurotransmitter will bind to receptors on Neuron B. This excess neurotransmitter will cause increased firing from neuron B. Neuron B responds to the excess stimulation by undergoing genetic changes which cause it to restructure some parts (growing dendritic spines which increase surface area for synapse formation and neurotransmitter binding), and expressing more neurotransmitter receptors in the synaptic region, so it is more sensitive to neurotransmitter.

Now, even when Neuron A is firing normally, neuron B will be much more exciteable than it was before the ‘experience’, as it is much more sensitive to lower amounts of neurotransmitter.

…if the handwriting is even legible…

Now that article is referring to an enzyme called Protein Kinase M. Protein Kinases are a class of enzymes which carry out a whole plethora of crucial life supporting roles in most eukaryotic organisms (if not others… but I don’t know so much about the role of protein kinases in bacteria and archaea, if they have a role at all. Depends when the protein kinase evolved I guess). In this case, protein kinase M is important in maintaining the increase in sensitivity of Neuron B by modifying particular proteins with a Phosphate ion.

I always enjoy learning about the atomic and chemical processes that underly our existence! Here is a phosphate ion - one of the key players in forming and maintaining memories. 

As to which proteins it phosphorylates in the case of memory persistence, I am unsure. I know that Protein Kinase A and Protein Kinase C (closely related proteins to Protein Kinase M) are involved in phosphorylating particular neurotransmitter receptors (AMPA if you’re interested) and proteins which ‘switch on’ the expression of certain genes (known as transcription factors).

With regards to the experiment in the paper, it seems that inhibiting the function of protein kinase M prevents memory persistence, as the neuron which has changed with experience (as that is what memory is - a neuronal change caused by an ‘experience’ or stimulus) is not ‘saving the new changes’ - to draw a parallel to a Microsoft word file. This process of neurons changing with experience is known as Synaptic Plasticity.

Even this diagram is an oversimplification of memory formation. I think the main point of this diagram is to show the phosphorylation events. There are the gliotransmitters, the Mg2+ ion and various other chemicals and molecules involved. (Diagram from Protein Phosphorylation and Long-term synaptic plasticity by A Barria et al, 2001, from the Encyclopedia of Life Sciences)

Now in reality, there is more than just neuron A and neuron B involved. There are whole networks of thousands of neurons, all interconnecting and forming thousands of synapses. A memory as we know it doesn’t just rely on 2 neurons. These principles are thus extrapolated to occur in a whole network of neurons. And once the memory is ingrained in one network of neurons, it seems to also be stored elsewhere in the brain, as removal of the hippocampi (the main candidate for the region of memory formation in the brain) doesn’t really delete old memories - though it does inhibit the formation of new long term memories.

And hell, memory formation goes past just using neurons. Our under-rated friends, the neuroglia are also vital in memory formation. A type of glial cell known as an astrocyte (the most abundant glial cell in the brain) releases cofactors into the synapse along side the firing presynaptic neuron, and these gliotransmitters bind to the receptors with the neurotransmitters to potentiate their response. Indeed, in very recent experiments on mice, it was found that preventing release of the gliotransmitter D-serine inhibited memory formation. The role of glia in memory formation is still a relatively new field, and there is a lot to learn just yet. 

And for the record, the website has it wrong. Aplysia is a sea slug, not a snail. It looks like this: -

(Aplysia releasing ink from its mantle)

It has had a pivotal role in the understanding of the biochemistry behind learning and memory. Eric Kandel won the Nobel Prize for elucidating the fundamental biochemical principles of memory formation (neuron sensitisation/habituation), from his work on Aplysia.

So… yeah. That’s memory formation in a nutshell. It’s a complex process which underpins our personality, our character and how we respond to events. There’s still a lot to do in the study of memory and learning, but the implications of a sound understanding of these systems are huge. One day, we may even be able to record memories, delete memories, copy memories… plant memories.