The astrocyte odyssey

Abstract

Neurons have long held the spotlight as the central players of the nervous system, but we must remember that we have equal numbers of astrocytes and neurons in the brain. Are these cells only filling up the space and passively nurturing the neurons, or do they also contribute to information transfer and processing? After several years of intense research since the pioneer discovery of astrocytic calcium waves and glutamate release onto neurons in vitro, the neuronal-glial studies have answered many questions thanks to technological advances. However, the definitive in vivo role of astrocytes remains to be addressed. In addition, it is becoming clear that diverse populations of astrocytes coexist with different molecular identities and specialized functions adjusted to their microenvironment, but do they all belong to the umbrella family of astrocytes? One population of astrocytes takes on a new function by displaying both support cell and stem cell characteristics in the neurogenic niches. Here, we define characteristics that classify a cell as an astrocyte under physiological conditions. We will also discuss the well-established and emerging functions of astrocytes with an emphasis on their roles on neuronal activity and as neural stem cells in adult neurogenic zones.

Figure 1. Diagram summarizing the sequence of neuron and glia development

The generation of the different neuronal and glial cell occurs in a temporally distinct yet overlapping pattern. In rodents, neurogenesis (e.g. generation of projection neurons) peaks at embryonic day 14, astrocytogenesis at postnatal day (P) 2, and oligodendrocytogenesis at P14. The generation of interneurons starts during embryonic life and continues postnatally. However, postnatal interneuron generation is essentially restricted to the olfactory bulb and the dentate gyrus. Astrocytes can be generated from several sources: radial glia during the perinatal life, glia restricted progenitors in the ventricular zone during embryonic life, and from glia restricted progenitors generated from transit amplifier during postnatal and adult life.

Figure 2. Morphology of astrocytes

(A and B) Photographs of astrocytes recorded in the hippocampus and filled with lucifer yellow during patch clamp recording. Immunostaining for GFAP was overlaid with the lucifer yellow fill. The cell in (A) displays a typical stellate morphology and strongly stains for GFAP, but does not display dye coupling. The cell in (B) displays dye coupling to other cells and send a process ensheathing a blood vessel typical of an astrocyte, but does not stain for GFAP.

Figure 3. The well-established functions

Astrocytes have several homeostatic functions maintaining a viable nervous system environment for neurons. These functions include: (1) providing metabolic support for neurons (section 3.5), (2) taking up K⁺ and neurotransmitters (sections 3.3 and 3.4, respectively), (3) Synaptogenesis (section 3.1), angiogenesis (sections 3.2.1), and BBB maintenance (section 3.3.2).

Figure 4. Astrocyte interactions with the vasculature

(A) Astrocytic processes ensheath blood vessels, including arterioles, which are composed of endothelial cells and smooth muscles cells (note shown on the diagram). The smooth muscle cells allow the vessels to contract or dilate. Neuronal activity induces mGluR activation in astrocytes leading to the synthesis of arachidonic acid (via PLA₂, not shown) and the formation of downstream messengers, including prostaglandins (PGs) and epoxyeicosatrienoic acid (EETs) via Cox2 and P450, respectively. PGs (in particular PGE2) and EETs induce vessel dilation. AA can also pass from astrocytes to smooth muscle cells where its downstream product 20-hydroxyeicosatetraenoic acid (20-HETE) induces vasoconstriction. In addition the activation of Ca²⁺ activated K⁺ channels in astrocyte endfeet and the efflux of K⁺ from astrocytes and subsequently from smooth muscle cells has been suggested to modify vascular tone by hyperpolarization and relaxation of smooth muscle cells, but this does not occur in the retina (See Metea et al, 2007). (B) Glutamate uptake into astrocytes is accompanied by Na⁺ entry leading to Ca²⁺ elevation as a result of Na⁺/Ca²⁺ exchange. Together Na⁺ and Ca²⁺ can stimulate glucose uptake from the blood into astrocytes via GLUT1. (C) One newer hypothesis is whether changes in blood vessel diameter can affect the biology of astrocytes via activation of stretch-activated channels that can be permeable to Ca²⁺ or other ions.

Figure 5. Astrocyte interactions with synapses

(A) Astrocytes encapsulate synapses including spines. This ensheathment allows spines to remain stable. At the molecular level, the ephrin-A3/EphA4 receptor signaling between astrocytic processes and spines has been shown to regulate the morphology of dendritic spines. In the absence of astrocytic processes, motile filopodia extend from dendrites. The astrocytic contact allows the filopodia to transform into a mature spine. (B) Astrocytes are an active synaptic partner. Not only they take up glutamate via high affinity transporters (not shown here), but they sense glutamate escaping synaptic clefts and release neuroactive substances upon glutamate receptor activation and intracellular Ca²⁺ elevation. Neuroactive substances include glutamate that is released via either vesicles or via Ca²⁺-dependent chloride channels, or both. Glial glutamate activates extrasynaptic receptors, including NR2B, on neurons leading to changes in synaptic integration.

Figure 6. The SVZ astrocyte

(A and B) Photographs of GFP fluorescence (green) with immunostaining for GFAP (red). The image in the white squares in (A) is shown at higher magnification in (B). Astrocytes in the lateral SVZ have there cell bodies either touching the ventricle or touching the striatum. (C) Photographs of a DIC image and corresponding image of a lucifer yellow-filled astrocyte. The recorded astrocyte has a process projecting toward the lateral ventricle and displays dye coupling. Scale bar: 20 μm. (D) Scheme illustrating the arrangements of the different cell types in the SVZ. SVZ astrocytes (orange) ensheath neuroblasts (blue) and transit amplifying progenitors (green, also called transit amplifiers) are scattered among SVZ cells. Ependymal cells line the lateral ventricle. SVZ astrocytes and ependymal cells display uptake mechanisms for K⁺, GABA and glutamate.