Hippocampal astrocytes represent navigation space

Hippocampal place cells, which display location-specific activity, are known to encode spatial information. A recent study in PLOS Biology by Curreli and colleagues shows that hippocampal astrocytes are implicated in encoding complementary spatial information, suggesting the existence of glial place cells.

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 virtual 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 location-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 distinct 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 possible 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 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 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 hippocampal astrocytes.
These results further raise a conspicuous unanswered question: What spatial information do hippocampal astrocyte Ca 2+ signals encode? Does astrocyte spatial encoding involve nontrivial 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 integrating 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 necessary 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 perspective 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 navigating 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.