ReviewThe multifaceted subventricular zone astrocyte: From a metabolic and pro-neurogenic role to acting as a neural stem cell
Introduction
Until recently, it was thought that the generation of neurons in mammals occurred only during the embryonic period. By now it has been clearly demonstrated that new neurons continue to be generated in two regions of the adult brain, the subgranular zone (SGZ) of the dentate gyrus of the hippocampus and the ventricular–subventricular zone (V–SVZ) lining the lateral wall of the lateral ventricle. The neural progenitor cells (NPCs) in the V–SVZ give rise to transit amplifying precursors that themselves give birth to neuroblasts (Doetsch et al., 1999). These neuroblasts migrate tangentially to the olfactory bulb to become interneurons (Luskin, 1993, Lois et al., 1994). The NPCs of the V–SVZ arise during embryonic development and persist into adulthood. In the embryonic brain, a very particular cell type, called radial glia was initially described with the classical Golgi silver impregnation method at the end of nineteenth century (Magini, 1888, Ramon y Cajal, 1995, Retzius, 1894), and found to provide a scaffolding for the migration and placement of newborn neurons (Rakic, 1971). Radial glia were found to possess another critical function, first identified in songbirds, which is their ability to proliferate in the ventricular zone coinciding with sites of neurogenesis (Alvarez-Buylla et al., 1990). This finding was later confirmed and expanded in the embryonic mammalian brain and it is now well-accepted that radial glia act as NPCs and generate the majority of neurons in the embryonic brain (Miyata et al., 2001, Noctor et al., 2001, Malatesta et al., 2003). After birth, most radial glia transform into parenchymal astrocytes throughout the central nervous system (Schmechel et al., 1979, Voigt, 1989, Alves et al., 2002, Merkle et al., 2004), except in the two postnatal neurogenic regions, where radial glia act as NPCs and generate the three main neural cell types, including neurons, oligodendrocytes, and astrocytes (Kriegstein and Alvarez-Buylla, 2009). These NPCs persist throughout adult life in these two regions, in all mammalian species examined including humans (Bonfanti and Peretto, 2011). The exact fate of NPCs is being more carefully examined using novel labeling methods and lines of transgenic mice based on the concept that not all NPCs are equal in terms of their fate. NPCs in the dorsal V–SVZ were shown to generate oligodendrocyte precursors (OPCs) that migrated radially into the white matter (Marshall et al., 2002, Marshall et al., 2003, Menn et al., 2006). Nevertheless, the generation of neurons predominates over that of oligodendrocytes (Menn et al., 2006) although OPC production is significantly increased following injury, in particular demyelination (Picard-Riera et al., 2002, Aguirre et al., 2007, El Waly et al., 2014)). Importantly, it was elegantly shown that a single NPC exclusively generates OPCs or immature neurons, but not both (Ortega et al., 2013). Here, we do not distinguish between OPC or neuroblast-fated NPCs with respect to their properties.
In the V–SVZ, It was found that NPCs share many features of mature astrocytes including morphological and biophysical characteristics as well as antigens such as glial fibrillary acidic protein (GFAP) (Doetsch et al., 1997, Doetsch et al., 1999, Liu et al., 2006). Here, we will focus on describing specific properties of the V–SVZ NPCs, referred to as V–SVZ astrocytes. We will first describe the unique set of markers, the morphology, and the neurophysiological characteristics of V–SVZ astrocytes. We will discuss the fact that although the population of V–SVZ astrocytes seems homogenous with respect to their neurophysiological properties (electrophysiological, coupling, neurotransmitter receptors, and transporters expression) they differ with respect to their neurogenic properties, e.g., stages of the cell cycle, quiescence versus activation state, neurogenic fate, and transcription factor expression. Finally, we will describe two functions of V–SVZ astrocytes, their coupling to blood vessels and their neurogenic supportive role consisting of providing guidance and survival cues to migrating newborn neurons.
Section snippets
Morphological and antigenic properties defining V–SVZ astrocytes
Two main populations of GFAP-positive cells and a third more discrete population were observed in the V–SVZ (Jankovski et al., 1996, Doetsch et al., 1997)(Fig. 1). The two main populations were called type B1 and B2 cells (Doetsch et al., 1997), both of them exhibiting characteristics of astrocytes. B1 cells were initially described morphologically with a simple fusiform cell body, only 2 to 3 processes with few branches (Jankovski and Sotelo, 1996). These cells were identified as the NPCs of
Neurophysiological characteristics of V–SVZ astrocytes
Studies during the last decade have characterized the neurophysiological properties of SVZ astrocytes. Because the V–SVZ is very densely populated by several cell types, including V–SVZ astrocytes, transit amplifying cells, neuroblasts, ependymal cells, and microglial cells, it is complicated to identify V–SVZ astrocytes from the other cell types in acute brain slices without a counter-staining. Thus, most neurophysiological studies took advantage of transgenic mice, such as the hgfap-GFP mice
Do all V–SVZ astrocytes possess the same neurophysiological properties?
The neurophysiological characteristics of V–SVZ astrocytes have been measured in hgfap-GFP-positive V–SVZ astrocytes without distinguishing the different subpopulations mentioned earlier leading to the conclusions that neurophysiological properties described in the previous chapter are homogenous among these cells. For example, all V–SVZ astrocytes were reported to express the neurotransmitter transporters GLAST, GLT-1, and GAT4 as well as connexin 43 resulting in functional coupling. All V–SVZ
Metabolic coupling in the V–SVZ niche
In the brain, neuronal activity dictates transfer of oxygen and nutrients from the blood stream into active neuronal assemblies through a local “neurovascular coupling” in part carried out by astrocytes (Giaume et al., 2010). Although SVZ cells do not generate action potentials, the V–SVZ contains cells undergoing proliferation, which is a metabolically demanding process (Bolanos et al., 2010). It is thus not completely surprising that the V–SVZ contains a large network of blood vessels and in
V–SVZ astrocytes support neuroblast survival during migration by releasing glutamate
Type B1 cells generate neuroblasts that migrate a long distance to the olfactory bulb through the rostral migratory stream (RMS). While V–SVZ astrocytes don’t express any ionotropic glutamate receptors, neuroblasts express functional AMPA (Platel et al., 2007), kainate (Platel et al., 2008), NMDA receptors (Platel et al., 2010), and mGluR5 (Di Giorgi Gerevini et al., 2004, Platel et al., 2008), shown by using neurophysiological recordings in acute slices and immunohistochemistry in fixed
Conclusion
The subventricular zone is a more complex region than previously appreciated in terms of its cellular diversity among a similar group of cells, like NPCs. The neurogenesis community is progressively finding new markers and generating new genetic tools such as new lines of transgenic mice to better characterize the morphological and neurophysiological properties of NSCs. Additional work is also needed to better identify the similarities and the differences between the neurogenic domains in the
Acknowledgments
Platel Jean-Claude is supported by the Institute National de la Santé et de la Recherche Médicale.
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