Abstract

Astrocyte Diversity Across Brain Regions

Astrocytes are critical non-neuronal cells of the central nervous system (CNS) that maintain precise environmental conditions for neurons and their connections. The complex structural and molecular properties of astrocytes enable these cells to play major roles including extracellular ion maintenance, neurotransmitter recovery and regulation of cerebrovasculature. Of particular interest for this mini-review article is the protoplasmic astrocyte which has a sponge-like appearance and closely interfaces with neurons, synapses and cerebrovasculature. These cells are extremely complex, enveloping neuronal cell bodies and synapses with fine processes, and surrounding blood vessels with endfeet. These processes are loaded with specific molecular machinery allowing these cells to fulfill many functions including removing neurotransmitters and ions, secreting neuroactive substances that regulate synapses, regulating energy substrates and exchanging nutrients with vasculature.

Astrocytes were initially defined by their star-shaped morphology in the 19th century. Today, however, it is more greatly appreciated that astrocytes display an array of morphological and functional features that reflect the brain circuitry in which they surround. In some regions of the CNS, astrocyte morphology is so dramatically different that it can be used to identify the boundaries of anatomical regions (Emsley and Macklis, 2006). However, recent studies have shown that differences between astrocytes go well beyond their morphology, with some CNS astrocytes displaying distinct molecular and functional properties that are exquisitely matched to the function of neighboring neurons. Below are several examples of astrocytes from different CNS regions that possess distinct structural and/or functional properties with a clear adaption to nearby circuitry (Figure ​(Figure11).

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Figure 1

Astrocyte diversity across brain regions. Schematics showing region specific properties and functions of different astrocyte types. (A) Müller glia (MG) of the retina are radially polarized astrocytes that span all retinal layers. With endfeet attached to the inner retinal surface and soma in the inner nuclear layer (INL), they elaborate processes into every layer of the retina. MG facilitate the transmission of light (rainbow) from the inside of the eye (up) across the retina to the photoreceptors in PL. GL, granule layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; PL, photoreceptor layer. (B) BG are radially polarized astrocytes that manage the glutamatergic synapse-rich neuropil of the cerebellar cortex. (B, inset) Glutamate released at PF-PC synapses activates calcium permeable ionotropic AMPA receptors and causes and influx of Ca²⁺ into astrocytes. PC, Purkinje cell; BG, Bergmann glia; ML, molecular layer; PCL, Purkinje cell layer; GCL, granule cell layer; PF, parallel fiber. (C) Astrocytes in arcuate nucleus of the hypothalamus are critical regulators of satiety and energy homeostasis. They respond directly to the hormones insulin, leptin and ghrelin by modulating glucose transport and the synaptic activity of hypothalamic neurons. Ultimately, astrocytic metabolic hormone signaling is necessary for the homeostatic maintenance of blood glucose levels and the regulation of feeding behavior. (D) Astrocytes of the dorsal suprachiasmatic nucleus (dSCN) are critical players in the maintenance of circadian rhythm. (D, upper panel) The levels of calcium signaling neurons and astrocytes are anti-phase; neurons are active during the day while astrocytes are active during the night. (D, lower panels) Simulated plots of periodic wheel running activity of mice under multiple conditions. The motor activity of mice is largely constrained to dark periods during equal length light and dark cycles. When kept in constant darkness, circadian period is only slightly shifted as revealed by their motor activity. However, when the intrinsic circadian clock of dSCN neurons is lengthened, the mice display a large shift in the periods of motor activity. Interestingly, when the same manipulation to lengthen the intrinsic circadian period is performed on dSCN astrocytes, the mice show a shift in behavior that resembles the neuronal manipulation.

Developmental Patterning and Interregional Astrocyte Heterogeneity

Many of the differences between astrocytes likely spawn from distinct developmental programs which result in specific cellular identities for a given brain region. Given the need of astrocytes to fulfill specific support roles of diverse neuron populations it is not surprising that astrocyte heterogeneity mirrors neuronal diversity. But how are different astrocytes actually created throughout the brain? Astrocytes generally come from related progenitors as the neurons that they support. Thus, patterning and specification of astrocytes may follow the same fundamental principles as those guiding neuronal development within a given brain region. This might ensure that astrocytes acquire specific properties that are configured for the surrounding neuronal population.

Environmental Cues and Intraregional Heterogeneity of Astrocytes

The patterning of the nervous system provides a mechanism to generate extensive cellular diversity. Interestingly, astrocytes can show diversity even within a defined CNS region. One of the most striking examples of intraregional heterogeneity is the stark difference between the two major astrocytes of the cerebellum, BG and velate astrocytes (VAs). BG and VAs are derived from the same progenitor pool (Kita et al., 2013), yet have contrasting morphologies and gene expression profiles. Remarkably, it is persistent signaling from adjacent neurons that is responsible for maintaining the unique gene expression profile of mature BG (Farmer et al., 2016). In other brain regions, astrocyte heterogeneity appears to be more complex. In the striatum, intermixed astrocytes and neurons from multiple progenitor pools interact indiscriminately yet astrocytes show selective interactions with specific circuits (Martín et al., 2015; Torigoe et al., 2015). Single-cell RNAseq of the striatum indicates that unlike other cells of the striatum, astrocytes do not segregate into discrete populations and therefore do not appear to form well-defined subtypes (Gokce et al., 2016). In the cerebral cortex, astrocyte can display diverse expression patterns coupled with layer-specific molecular heterogeneity. The intraregional heterogeneity of cortical astrocytes is easily revealed by immunolabeling for the inward-rectifying potassium channel Kir4.1, the GABA transporter GAT3/Slc6a11, the glutamate transporters EAAT1/GLAST and EAAT2/GLT1, and the water channel aquaporin 4 (AQP4). GAT3 and Kir4.1 are particularly enriched in Layers 2/3 and Layer 5 (Conti et al., 2004; Moroni et al., 2015), whereas Aqp4, glial fibrillary acidic protein (GFAP) and Connexin-43/Gja1 show strong expression in Layer 1 and in pial astrocytes in the mouse (Zeisel et al., 2015).

Context-Dependent Signaling and The Expansion Astrocyte Diversity

How do intraregional differences in astrocytes arise? A creative solution is to enable astrocytes to use environment cues to configure their properties within a given brain region. This type of mechanism would ensure that astrocytes are precisely matched to neighboring neurons and associated circuitry and, moreover, be able to dynamically shift their functional and/or structural properties to adapt to new environmental situations. Recent studies have now found that components of multiple signaling pathways that pattern the developing CNS are enriched in mature astrocytes (Cahoy et al., 2008) and, importantly, persistent signaling through specific signaling pathways is required to maintain astrocyte properties in the adult brain. Culturing astrocytes with neurons causes increased astrocytic elaboration and the induction of hundreds of astrocyte genes including Glast, GLT1, AQP4 and GAT3 (Hasel et al., 2017).

Conclusion and Future Perspectives

Astrocytes are a remarkably heterogeneous population of cells that contain distinct properties unique to the brain regions in which they reside. While developmental patterning events are critical for fostering astrocyte heterogeneity, they cannot fully account for the production and maintenance of such diverse astrocyte types. Consistent with this, studies have now shown that mature astrocytes depend on a number of intercellular signaling pathways to maintain their specific properties by regulating expression of receptor/channel/transporter expression, their quiescence and morphological properties. We currently do not know the full complement of the pathways that drive gene expression in mature astrocytes or how these types of pathways interact to establish specific gene expression profiles. Moreover, there are many questions regarding the origin and specificity of context-dependent signaling underlying astrocyte diversity and under what circumstances this signaling can change. Interestingly, chronic disruption of signaling pathways related to Shh, Notch and FGF in the adult brain leads to astrocyte reactivity which is reminiscent of pathological states in CNS injury/disease. Thus, the ability of astrocytes to detect and utilize environmental cues may serve a dual purpose by: (1) generating further astrocyte diversity; and (2) maintaining healthy, non-reactive astrocyte phenotypes. Further studies are needed to understand the fine balance between these scenarios and reveal potential new mechanisms allowing astrocytes to transition from a healthy to a disease state. Ultimately, understanding how astrocyte heterogeneity is generated will allow us to better understand fundamental properties of the CNS and potentially improve brain/spinal cord function following injury or disease.

Author Contributions

WTF conceived, researched and wrote this review. KM assisted in writing and editing.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer HH and handling Editor declared their shared affiliation.

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