Resolving Astrocyte Heterogeneity in the CNS

Abstract

Astrocytes play essential roles in nearly all aspects of brain function from modulating synapses and neurovasculature to preserving appropriate extracellular solute concentrations. To meet the complex needs of the central nervous system (CNS), astrocytes possess highly specialized properties that are optimized for their surrounding neural circuitry. Precisely how these diverse astrocytes types are generated in vivo, however, remains poorly understood. Key to this process is a critical balance of intrinsic developmental patterning and context-dependent environmental signaling events that configures astrocyte phenotype. Indeed, emerging lines of evidence indicate that persistent cues from neighboring cells in the mature CNS cooperate with early patterning events to promote astrocyte diversity. Consistent with this, manipulating Sonic hedgehog (Shh), Notch and fibroblast growth factor (FGF) signaling in the adult brain, have profound effects on the structural, morphological and physiological state of mature astrocytes. These pathways may become disrupted in various neurological diseases and contribute to CNS pathology. This mini-review article focuses on how context-dependent environmental cues cooperate with intrinsic developmental patterning events to control astrocyte diversity in vivo in order to promote healthy brain function.

Keywords: Bergmann glia; Fgf; Müller glia; Sonic hedgehog (Shh); astrocyte heterogeneity; astrocyte-neuron interactions; notch.

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.