Memories are made of this: two proteins

Two proteins work together to help us rapidly make memories of new places, new research reveals.

A study published in the journal Proceedings of the National Academy of Sciences sheds light on the molecular mechanisms of memory and may also improve understanding of cognitive disorders such as schizophrenia and Fragile-X syndrome.

As a memory of a new experience is made, a new pattern of connections forms between neurons. New connections may be made, while existing ones are strengthened and others weakened. It’s known that this requires an ample supply of new proteins. Indeed, neural activity associated with a novel experience, such as entering a new place, causes our brain cells to ramp up protein production.

But as senior author Weifeng Xu of Massachusetts Institute of Technology’s Picower Institute for Learning and Memory points out, “We still had several layers of questions.”

Namely, which proteins are necessary for the formation of new memories? And for how long are they are needed? To find out, Xu and her team took a closer look at protein production in the hippocampus, a region of the brain critical for memory formation.

In a memory test, mice were introduced to a new chamber where they received a foot-shock. When later returned to the chamber, if they froze in anticipation, this indicated they remembered.

A drug was used to temporarily block general production of proteins in the brains of mice either before, during, or after they were introduced to the new environment. If protein production was disrupted either prior to or precisely when encountering the chamber, the mice had difficulty forming the memory. But if protein production was disrupted after this point in time, there was no effect. This suggested that protein production during memory formation is fast but fleeting.

Xu and her colleagues then examined messenger-RNA (mRNA) levels to determine which proteins are being made.

During protein production, as the gene is read, mRNA is produced, and tells the cell’s protein-making factory, the ribosome, how to make the protein required. Thus, mRNA is a critical intermediate step in the process, and examining mRNA levels can reveal which proteins were recently produced.

The researchers discovered that memory formation is associated with a singular increase in mRNA levels of the gene Ngrn, which codes for a protein called neurogranin, which was first linked to memory formation in 2017.

When they blocked production of neurogranin in mice, the rodent struggled to form new memories when encountering a new location. If neurogranin was added back in, this effect was reversed.

Thus, formation of experience-related memories appears to rely on rapid production of high levels of neurogranin, but further investigation revealed that another protein, called FMRP, is also critical.

It turns out, FMRP interacts with the mRNA of neurogranin, enabling it to relay its protein-making instructions. When the gene for FMRP was inactivated, mice had difficulty forming new memories.

Xu wonders if FMRP enables the extremely quick production of neurogranin.  

“We really are at the early stage of understanding why it is so fast,” says Xu. “Novel experience exposure may enhance the rate of synthesis somehow.”

She wonders if an abundance of neurogranin mRNA is always ready, and FMRP allows it to be translated into protein on cue.

Intriguingly, abnormalities in the function of both neurogranin and FMRP have been linked with cognitive and neurodevelopmental disorders. Neurogranin has been linked with schizophrenia, and mutations in FMRP, which stands for “Fragile X Mental Retardation protein”, have been associated with Fragile X syndrome and autism.

That these proteins are central to memory formation could provide new insight into how their disruption in the hippocampus and elsewhere in the brain might contribute to these disorders.