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  • KSBNS 2024

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Perspective

Exp Neurobiol 2024; 33(6): 263-265

Published online December 31, 2024

https://doi.org/10.5607/en24033

© The Korean Society for Brain and Neural Sciences

Can Astrocytes Store and Recall Memory? Yes, Indeed!

Mridula Bhalla and C. Justin Lee*

Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Korea

Correspondence to: *To whom correspondence should be addressed.
TEL: 82-42-878-8185, FAX: 82-42-878-9151
e-mail: cjl@ibs.re.kr

Received: December 29, 2024; Revised: December 31, 2024; Accepted: December 31, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Astrocytes have been known to support neuronal function, but until now, memory storage and recall has thought to be largely controlled by neurons. In this article, we shed light on recent research published by Williamson et al. that, for the first time, shows astrocytes to participate in memory formation and recall.


Keywords: Astrocytes, Memory, Engram

For centuries, the ability of the brain to create, store, and recall memories has been a marvel and explored extensively. So far, many scientists have expanded the cellular role of neuronal ensembles, called “engrams”, in learning and memory recall. For long it has been believed that neurons are master regulators of memory in the brain. Scientists at the Baylor College of Medicine, led by Benjamin Deneen, have discovered for the first time that star-shaped cells in the brain, called astrocytes, activate in response to memory formation and regulate memory recall [1].

Astrocytes are non-neuronal glial cells in the brain and spinal cord. Named after their star-like shape, they were thought to initially be the “glue” or homeostatic cells of the brain. These cells play a supportive role in the nervous system and have now been reported to work in harmony with neuronal engrams to regulate memory. This finding has forever changed the way we see learning and memory recall.

In their study, Williamson and Kwon et al. performed a series of experiments to confirm the activation of astrocytes in the hippocampus of mice during memory formation and to study the effects of blocking this activation on memory. The authors found that chemogenetic activation of neurons in the hippocampus elicited astrocytic expression of c-fos, an early transcriptional gene associated with cellular activation. Moreover, when they silenced the gene encoding for Fos in astrocytes, they found that animals struggled to learn and recall a simple contextual fear conditioning task as well as a spatial memory task, suggesting the importance of astrocytic activation in learning and memory formation.

The authors termed these “learning-associated astrocytes” (LAAs) and observed that mice trained in a fear conditioning paradigm exhibited increased calcium activity in these ensembles. Of note was that these LAAs reside in proximity to the engram neurons that store the fear memory and that more synaptic connections formed within the territories of these astrocytes during the learning paradigm (Fig. 1, green synapses formed within the domain of a c-fos positive astrocyte). Chemogenetic activation of these LAAs following learning was sufficient to induce long-term potentiation (LTP), a feature of synaptic plasticity. Surprisingly, when the mice were placed in a previously untested context (one without any fear association) and these LAAs activated, the mice responded by freezing, thereby indicating controlled recall of the fear-associated memory. These findings are crucial in understanding how astrocytes and neurons communicate during memory formation and retrieval and incite further interest in the molecular factors behind this communication. It does bring to question the molecular factors that may be involved in this astrocyte-neuron communication. Further studies would be imperative to uncover the gliotransmitters participating in this interaction.

The authors pinpointed this astrocytic control over memory recall to NF1A, a nuclear protein involved in the control of gene expression. They found that NF1A was elevated in LAAs, and when the gene encoding for NF1A was deleted, animals failed to recall the memory associated with that specific LAA. While NF1A has previously been associated with memory circuits, this study was the first to report the function of this protein in astrocytes associated with memory. While NF1A is known to be associated with the regulation of gene expression, further research to discover the molecular pathways modulated by its expression in memory formation would be essential in dissecting the importance of astrocytes in learning and memory. Additionally, it would be apropos to conduct experiments using different behavioral paradigms to study the role and response of astrocytes in brain regions other than the hippocampus.

An independent group of researchers, led by Bong Kiun Kaang at Seoul National University, also utilize a genetic tool to visualize connections formed between memory-encoding engram neurons and astrocytes, called astrocyte e-GRASP [2]. They observed that astrocytes form more connections with memory-encoding neurons than non-engram neurons, which are stabilized further by neuronal activity. However, they claim that this increased number of astrocyte-neuron connections is due to reduced disappearance of synapses in the absence of neuronal activity rather than increased formation of connections, backed by experiments in cultured cells. While Williamson and Kwon et al. present a compelling case of LAA-surrounding engram neurons forming more synaptic connections, it remains to be seen whether these are nascent or persisting synapses.

More connections indicate more control and interaction between the astrocytes and neurons for the regulation of memory formation and storage. The concept of the tri-partite synapse, suggested decades ago by Araque, mentions glia as the “unacknowledged partner” [3]. This now seems to be changing, with reports such as the ones mentioned above revealing the extensive involvement of astrocytes and the tripartite synapse in memory.

The knowledge that astrocytes are essential in memory formation and retrieval might be helpful to understand diseases associated with memory loss (vascular dementia, Alzheimer’s disease) or dysfunctional repetitive recall (PTSD, schizophrenia). The findings from this study bring to light the bidirectional communication between astrocytes and neuron engrams that is essential in memory formation and recall and provide a new perspective to the previously neuro-centric approaches to memory. This work can be ground-breaking in modifying our approach toward understanding memory formation, storage, and recovery. However, the biochemical quanta used by astrocytes for the storage and retrieval of these memories needs to be explored to build and support a convincing argument for this astrocytic control of memory.

Fig. 1. Schematic diagram showing the formation of more synapses in the domain of c-fos-positive NF1A-expressing learning-associated neurons in the mouse brain during a fear conditioning task.
  1. Williamson MR, Kwon W, Woo J, Ko Y, Maleki E, Yu K, Murali S, Sardar D, Deneen B (2024) Learning-associated astrocyte ensembles regulate memory recall. Nature doi: 10.1038/s41586-024-08170-w.
    Pubmed CrossRef
  2. Kim J, Sung Y, Park HJ, Choi DI, Kim JI, Lee H, Jung MG, Noh S, Ye S, Lee J, Islam MA, Chun H, Mun JY, Kaang BK (2023) Astrocytic connection to engram neurons Increased after learning. bioRxiv (Preprint) doi: 10.1101/2023.01.25.525617.
    CrossRef
  3. Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22:208-215.
    Pubmed CrossRef