Memory Suppression Genes – Team Forgetful

September 14, 2021

Written by: Sara Taylor

In the past week alone, I have “lost” my phone in my one-bedroom apartment more times than I’d like to say. Each of the upwards of 20 times, I have found myself asking “why can’t I remember where I put it ?!?!” Happily, lots of people have been doing research to try to answer that very question. It turns out that there is an entire team of genes and the biological products they give rise to whose job it is to disrupt memory. Let that sink in – our body intentionally produces proteins that make us forget instead of remember. The genes that encourage forgetting are called “memory suppression genes”, while the genes that encourage remembering are called “memory enhancer genes”. Whether we remember something or not is influenced by these two opposing forces. 

In order to understand how memory suppression genes work, we need review the memory process. It can be a bit abstract, so let’s use the example of learning a new phone number. So, you are handed a phone number and the memory process begins. Stage one is called acquisition. Acquisition is when you first encode the information that you’ll want to remember. In this example, acquisition occurs when you read the phone number for the first time. Stage two is consolidation. In this stage, the information is put in a more stable and lasting form. You might repeat the phone number to yourself or come up with a gimmick (maybe it’s your dentist’s number and the last 5 numbers spell out teeth) to help with this process. In between stage two and four is a potential third stage – active forgetting— which we’ll touch on more later. Finally, stage four is retrieval. Retrieval occurs when you access the information that you successfully remembered. You retrieve the remembered number when you finally go to call your new contact.

Memory suppression genes can theoretically work at any of these four stages. So far, scientists have discovered memory suppression genes that work at three out of the four – acquisition, consolidation, and active forgetting. I’ll go through an example of each below.

Acquisition. First stop: encoding information. One way researchers have been able to learn more about this memory stage is to look at the olfactory system of flies. There is a gene (Rdl) that is expressed in the fly brain in neurons that are involved in olfactory processing (aka smelling) and olfactory memory (aka remembering smells). When the expression of this gene is increased, flies have a harder time than usual learning which smells are good and which are bad. On the other hand, decreasing the expression of Rdl improves smell learning. So, it looks like Rdl is definitely a memory suppression gene, but how does it affect memory? Rdl encodes part of a receptor, GABA-A, for the inhibitory neurotransmitter GABA. During memory acquisition, your brain is forming connections between neurons that encode different concepts (for example, between a string of numbers and the name of your new contact). GABA-A disrupts this process by quieting the signal of the neurons representing those concepts, essentially preventing a memory from being formed, and thus you have memory suppression at the first stage.

Consolidation. Next, you use consolidation to go from encoded information, which you can only remember on the scale of seconds, to long-term memory, which you can remember on the scale of minutes to years. Importantly, protein synthesis is necessary for the proper consolidation of memories. More specifically, certain proteins need to be produced in order to change the connections between neurons, aka the synapse, to allow for long-term memory. There are several genes that are involved in disrupting the protein-making process needed for consolidation. One is called PABP-interacting protein 2. It inhibits the work of a protein (called PABP for short) that helps with the synthesis of proteins important to memory consolidation. When researchers get rid of PABP-interacting protein 2 in mice, the mice performed better on tasks that test the consolidation of fear memories. By removing PABP-interacting protein 2, the protein synthesis necessary for consolidation was able to take place to a greater degree than usual, leading to better memory formation.

Active forgetting. The third stage of remembering sounds counterintuitive, but active forgetting helps to filter out information that you don’t necessarily need long term. There is a pair of proteins that have been implicated in active forgetting called Rac1 and Cdc42. Rac1 and Cdc42 both influence actin, tiny filaments that help form the interior structure of cells. By acting on actin, Rac1 and Cdc42 can actually undo the many changes happening at the synapse and inside each neuron involved in forming or maintaining a memory. Rac1 and Cdc42 differ in what kind of memories they affect. Through a series of experiments in mice, scientists showed that Rac1 enhances the forgetting of memories that have yet to go through consolidation. In flies, scientists showed that Cdc42 is involved in the forgetting of memories that have been well-consolidated and are stable. With processes to induce forgetting at difference stages, we can optimize the memories we do hold on to.

Forgetting can be a useful process. It can help us un-learn things. Imagine how much harder it would be to remember a new phone number if you remembered every phone number you’d ever heard! Forgetting can also help us take the overall lesson of a memory and apply it to new situations by getting rid of extraneous details. Memory suppression genes are there to help us with forgetting when it is useful, and sometimes when it is not. 

References:

Noyes, N. C., Phan, A., & Davis, R. L. (2021). Memory suppressor genes: Modulating acquisition, consolidation, and forgetting. Neuron. Read more at https://www.cell.com/neuron/fulltext/S0896-6273(21)00576-6