Where are my keys? What’s the name of that actor again? Did she say 3 or 4 o’clock? Forgetfulness is a part of life, albeit often an inconvenient one. If you find yourself wishing you would never forget anything, you may want to reconsider. Neuroscientists are beginning to uncover the molecular mechanisms of forgetting. With these new insights comes an understanding of forgetting not as a pesky flaw but rather a necessary feature for an efficient memory storage system in our brain.

Memory Storage and Retrieval

Although neuroscientists have just started to uncover the mechanisms of forgetting, we already know a lot about memory formation and consolidation.1 Brain cells, called “neurons,” form electrochemical connections with each other. Memories are encoded by changes in the strength of these connections. The strength of the connection between any two neurons is dependent on 1) the number of electrochemical contacts (“synapses”) between the two neurons and 2) the strength of each synapse. In this context, the phenomenon of forgetting is when we try to retrieve a stored memory and we fail. This could be due to a deficit in the formation of the memory, the integrity of the stored memory or simply our ability to retrieve it.1

Passive Versus Active Forgetting

Over the years, experimental psychologists have debated between two models of forgetting, termed “active” and “passive.” In the passive model, forgetting is the biological decay of neuronal connections that happens naturally over time. Meanwhile, “active forgetting” suggests that specific biological mechanisms strategically induce forgetting.1 The key piece of evidence that helped scientists choose between these two models is that recall promotes the storage of long-term memories.3 If forgetting were just due to biological decay, you would expect it to be harder to remember something over time, regardless of recall. The idea that recall improves memory suggests that it combats active biological mechanisms that drive forgetting. Due to this and other evidence, scientists have come to accept the active forgetting model. But wait. Does this mean your brain is plotting against you? Are your neurons conniving to make you forget your anniversary or your friend’s birthday?

In short, no. We have so many memories, and memory retrieval is so seamless, that it only makes sense to have an extremely efficient memory management system. Part of this efficiency is removing memories that are unused. In this way, active forgetting can be seen as beneficial. In essence, forgetting unused pieces of information allows for better recall of important information. We need constitutive forgetting of the unimportant in order to have efficient memory.

Forgetting Changes Synaptic Structure and Strength

As mentioned previously, memories are encoded by changes in the number of synaptic contacts between neurons and the strength of each connection. Recent studies show that the mechanisms of active forgetting also affect these parameters.

In 2017, researchers from Tsinghua University in Beijing implicated a role for the protein Rac1 in forgetting.2 As a measure for forgetting, fruit flies were trained to associate a particular odor with an unpleasant shock. After training, memory was assessed by giving the flies access to two chambers, one with the shock-associated odor and one with a neutral smell. Control flies mostly remembered which odor was associated with the shock and chose the other room. Flies with an overly active version of Rac1 forgot this association, while flies without Rac1 remembered the association even better than the control flies.

These experiments show that Rac1 promotes forgetting. So how exactly does it do this? Rac1 is a protein that modulates the structural filaments that give a cell shape. Because synapses are specialized structures of the neuronal cell, changes in cell shape dictate the number of synapses between two neurons. Overall, this suggests that active forgetting involves changes in synaptic structure and number.

Just a few weeks ago, a group of researchers from Germany implicated changes in synaptic strength during active forgetting.4 Syt3 is a protein that modulates synaptic strength via removal of synaptic receptors. The strength of a synapse can be defined by its number of receptors, which can be thought of as ears. The more receptors a neuron has, the better it can “hear” the incoming electrochemical signal from another neuron, and the stronger the connection between those neurons.

By promoting receptor removal from the synapse, Syt3 is thought to decrease synaptic strength and promote forgetting. When Syt3 knockout mice are placed in a pool of water with a hidden platform, they are able to learn where the platform is and can find it more quickly each time they are placed in the water. Syt3 knockout mice can remember where the platform is better than control mice, suggesting that they have impaired forgetting. However, when the same Syt3 knockout mice are then placed in a pool where the platform is in a different spot, they are unable to successfully learn the new location. Their inability to forget where the platform was before impedes their ability to learn the new information (“relearning”). In this way, forgetting can be thought of as a useful tool that enables us to learn new information.

Disease Implications

Some might think it would be beneficial to inhibit the molecular mechanisms of forgetting as a treatment for dementia. Yet others might get excited about the implications of promoting forgetting as a treatment for disorders such as post-traumatic stress disorder (reflected dramatically in the new Amazon TV series Homecoming). Although we are probably centuries away from targeting forgetting for any kind of treatment, if we ever do so it will be important to use caution. A “Goldilocks” level of forgetting is essential for a healthy mind. Too much forgetting impedes our ability to function, but too little can lead to learning deficits. One study shows that autism spectrum disorder risk genes confer an impairment in active forgetting.5 Considering this, some autism symptoms may be caused by loss of active forgetting and corresponding learning deficits. So, the next time you forget a song lyric or where on earth you put your glasses, take solace in the idea that your brain is engaging in a healthy process that is part of an efficient memory storage system.

References

  1. Davis, R. L., and Zhong, Y. (2017). The biology of forgetting — a perspective. Neuron, 95(3), 490–
  2. Shuai, Y., Lu, B., Hu, Y., Wang, L., Sun, K., and Zhong, Y. (2010). Forgetting is regulated through Rac activity in Drosophila. Cell, 140(4), 579–
  3. Hardt, O., Nader, K., and Nadel, L. (2013). Decay happens: the role of active forgetting in memory. Trends in cognitive sciences, 17(3), 111–
  4. Awasthi, A., Ramachandran, B., Ahmed, S., Benito, E., Shinoda, Y., Nitzan, N., and Burk, K. (2019). Synaptotagmin-3 drives AMPA receptor endocytosis, depression of synapse strength, and forgetting. Science, 363(6422), eaav1483.
  5. Zeidán-Chuliá, F., Rybarczyk-Filho, J. L., Salmina, A. B., De Oliveira, B. H. N., Noda, M., and Moreira, J. C. F. (2013). Exploring the multifactorial nature of autism through computational systems biology: calcium and the Rho GTPase RAC1 under the spotlight. NeuroMolecular Medicine, 15(2), 364–

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