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PRIMER
Hippocampal astrocytes represent navigation
space
Xinzhu YuID*
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana,
Illinois, United States of America
*xinzhuyu@illinois.edu
Hippocampal place cells, which display location-specific activity, are
known to encode spatial information. A recent study in PLOS Biol-
ogy by Curreli and colleagues shows that hippocampal astrocytes are
implicated in encoding complementary spatial information, suggest-
ing the existence of glial place cells.
The ability to perceive location and navigate through the space is a cognitive function crucial
for both humans and animals. It has been hypothesized that a “cognitive map” is constructed
in the mammalian brain based on spatial cues to represent the external environment. This
mental map could contribute to the formation of episodic memory that is linked to a specific
location and context. In search of the neurobiological basis of the cognitive map, O’Keefe and
Nadel first discovered place cells in the rodent hippocampus that become active when the ani-
mal travels to a specific location within its environment [1]. Subsequent studies have further
revealed additional key elements of the spatial navigation system, including grid cells, head
direction cells, and border cells. Collectively, the neuronal circuits of the hippocampal forma-
tion are believed to be responsible for constructing a detailed mental model of the external
space. Is this the entire story? A research article presented by Curreli and colleagues in the cur-
rent issue of PLOS Biology provides the first in vivo evidence that nonneuronal glial cells also
display location-dependent activity [2], raising important questions about whether and how
glial cells are involved in spatial navigation and cognitive map representation (Fig 1).
As the most numerous type of glial cells, astrocytes are morphologically complex and pres-
ent throughout the entire central nervous system (CNS). Their existence and close proximity
to neurons were depicted by pioneering neuroscientist SAU :PleasenotethatRamonyCajalhasbeenchangedtoSantiagoRam�onyCajalinthesentenceTheirexistenceandcloseproximityto::::Pleasecheckandcorrectifnecessary:antiago Ramo
´n y Cajal more than a
century ago. However, our understanding of astrocytes and their contributions to cognition is
still in its infancy. This is largely because astrocytes are electrically silent cells that lack mecha-
nisms to generate and propagate action potentials. Therefore, traditional electrophysiological
approaches provide little information about astrocyte activity and their function. Instead,
astrocytes display dynamic and extensive intracellular Ca
2+
signals that are believed to be the
primary mechanism mediating their communication with other cells [3]. These astrocytic
Ca
2+
signals occur throughout the entire cell (e.g., somata and processes), both spontaneously
and in response to neuronal activity. Mounting evidence has implicated astrocytic Ca
2+
signal-
ing as essential to modulating neuronal function and animal behaviors [4].
PLOS Biology | https://doi.org/10.1371/journal.pbio.3001568 March 8, 2022 1 / 4
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OPEN ACCESS
Citation: Yu X (2022) Hippocampal astrocytes
represent navigation space. PLoS Biol 20(3):
e3001568. https://doi.org/10.1371/journal.
pbio.3001568
Published: March 8, 2022
Copyright: ©2022 Xinzhu Yu. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Funding: The author received no specific funding
for this work.
Competing interests: The author has declared that
no competing interests exist.
Curreli and colleagues recorded intracellular Ca
2+
signals from hippocampal astrocytes
expressing a genetically encoded Ca
2+
indicator in head-fixed awake mice navigating in a vir-
tual reality environment [2]. Interestingly, the authors found that a population of astrocytes
displayed Ca
2+
responses that were modulated by the position of the mouse, indicative of loca-
tion-dependent activity that is similar to neuronal place cells. However, in contrast to neuronal
place cells, Ca
2+
signals from the somata and processes belonging to the same astrocytes may
respond to different spatial locations, i.e., different regions of a single astrocyte may have dis-
tinct place fields.
These are novel and intriguing findings; however, previous studies have demonstrated that
astrocyte Ca
2+
signaling largely reflects the activity of neighboring neurons [5,6]; thus, it is pos-
sible that the astrocytes are merely mirroring some spatial information conveyed by nearby
neuronal place cells. To account for this possibility, the authors simultaneously recorded Ca
2+
signals from both astrocytes and neurons in the hippocampus of awake mice navigating in the
virtual reality setup. Using an information theory–based analysis and a machine learning
approach, the authors showed that the spatial information encoded in astrocyte Ca
2+
signals is
not a simple copy of that stored in surrounding neurons. Specifically, animal’s spatial location
Fig 1. Cognitive map and underlying cellular mechanisms. A cognitive map encodes spatial information and allows
navigational planning. The hippocampus is a key structure containing cells responsible for constructing the cognitive
map in the mammalian brain. Hippocampal neurons known as place cells become electrically active when the animal
travels to specific locations within its environment. Using 2-photon in vivo Ca
2+
imaging, Curreli and colleagues
provide evidence that hippocampal astrocytes respond to spatial locations in a virtual reality environment with
elevations in their intracellular Ca
2+
signals. Moreover, the information contained by hippocampal astrocytes is not a
passive copy of nearby neuronal information. The tantalizing unanswered question is whether astrocytes are active
partners with neurons in generating a spatial cognitive map.
https://doi.org/10.1371/journal.pbio.3001568.g001
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was more accurately decoded with Ca
2+
signal data from neurons and astrocytes combined
than from neurons or astrocytes alone, suggesting additional information encoded by hippo-
campal astrocytes.
These results further raise a conspicuous unanswered question: What spatial information
do hippocampal astrocyte Ca
2+
signals encode? Does astrocyte spatial encoding involve non-
trivial computations rather than simple signal summation? Owing to its elaborate morphology,
a single hippocampal astrocyte territory is estimated to enclose around 90,000 synapses [7].
Thus, it is possible that hippocampal astrocyte Ca
2+
signals serve as a tuning factor by integrat-
ing diverse neuronal information and subsequently conveying synaptic regulation via ion
homeostasis, metabolic support, synaptic formation/removal, and neurotransmitter uptake.
Future computational modeling of these potential integrator functions may be fruitful, and
experimental manipulations of astrocyte ensembles and their corresponding subcellular Ca
2+
signals may provide direct evidence.
To understand how the CNS encodes, modifies, stores, and retrieves information, it is nec-
essary to explore the diverse cell populations that comprise the CNS. There is an emerging
consensus that the CNS cannot be satisfactorily understood solely as a collection of interacting
neurons. One significant missing aspect in our strategy to comprehensively understand the
CNS, particularly in the context of disease, is the largely unmet need to understand additional
cell types such as astrocytes. This work by Curreli and colleagues has provided a new perspec-
tive of astrocytic involvement in the domain previously considered to be uniquely neuronal. In
light of their stimulating results, there are many intriguing questions and further directions
that remain to be explored. First of all, given astrocytic place fields in a one-dimensional virtual
reality environment, how do hippocampal astrocytes behave in realistic environments? In
addition to encoding spatial locations, neuronal place cells are fundamental for goal-directed
navigation planning, episodic memory storage, and retrieval [8], presumably in conjunction
with neurons from other brain regions connected to the hippocampus. Although astrocytes do
not project beyond their local territories, can these local actions by astrocytes have a broader
effect on large-scale neural circuits by communicating with and modulating other cells in the
networks? Furthermore, sequential firing patterns of neuronal place cells activated while navi-
gating are replayed during sleep [9]. This mechanism is proposed to consolidate newly
encoded spatial memories. Can hippocampal astrocytes register previous spatial learning by
spatially tuned Ca
2+
signals and consolidate recent memory traces by offline replay of those
Ca
2+
signals? Last, are there equivalent astrocytic subpopulations responding to speed, head
direction, and boundaries to construct the complete spatial maps? With many new methods
and technological advances on the horizon [10], these questions will be ultimately tackled in
the foreseeable future.
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