PAGES_10_AG_019_BA.qxd:DCNS#42 30/08/09 1:25 Page 281 Translational research The role of astroglia in neuroprotection Mireille Bélanger, PhD; Pierre J. Magistretti, MD, PhD In the last two decades, intense research efforts aiming to provide a better understanding of astroglial cell function have revealed a number of previously unsuspected roles for these neural cells, which were long considered as relatively passive structural elements of the brain. It has now become quite clear that a plethora of cooperative metabolic processes and interdependen- cies exist between astrocytes and neurons. As a result of the growing appreciation of the role of astrocytes in both the normal and diseased brain, the traditional neuron- centric conception of the central nervous system (CNS) Astrocytes are the main neural cell type responsible for has been increasingly challenged. the maintenance of brain homeostasis. They form highly Astrocytes are territorial cells: they extend several organized anatomical domains that are interconnected processes with little overlap between adjacent cells, into extensive networks. These features, along with the forming highly organized anatomical domains1-3 which expression of a wide array of receptors, transporters, and are interconnected into functional syncytia via abundant ion channels, ideally position them to sense and dynam- gap junctions.4 These astrocytic processes closely ically modulate neuronal activity. Astrocytes cooperate ensheath synapses and express a wide range of receptors with neurons on several levels, including neurotransmit- for neurotransmitters, cytokines, and growth factors, as ter trafficking and recycling, ion homeostasis, energy well as various transporters and ion channels.5-11 In addi- metabolism, and defense against oxidative stress. The tion, astrocytes project specialized astrocytic endfeet critical dependence of neurons upon their constant sup- which are in close contact with intraparenchymal blood port confers astrocytes with intrinsic neuroprotective vessels, almost entirely covering their surface.12,13 properties which are discussed here. Conversely, patho- Together, these cytoarchitectural and phenotypical fea- genic stimuli may disturb astrocytic function, thus com- tures ideally position astrocytes to fulfill a pivotal role in promising neuronal functionality and viability. Using brain homeostasis, allowing them not only to sense their neuroinflammation, Alzheimer’s disease, and hepatic surroundings but also to respond to—and consequently encephalopathy as examples, we discuss how astrocytic defense mechanisms may be overwhelmed in patholog- Author affiliations: Laboratory of Neuroenergetics and Cellular Dynamics, Brain ical conditions, contributing to disease progression. Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, © 2009, LLS SAS Dialogues Clin Neurosci. 2009;11:281-295. Switzerland (Mireille Bélanger); Centre de Neurosciences Psychiatriques, CHUV, Département de Psychiatrie, Site de Cery, Lausanne, Switzerland (Pierre J. Keywords: astrocyte; astrocyte-neuron interaction; brain homeostasis; neuroin- Magistretti) flammation; Alzheimer’s disease; hepatic encephalopathy Address for correspondence: Prof Pierre J. Magistretti, EPFL SV BMI LNDC, SV 2511 (Bâtiment SV), Station 19, 1015 Lausanne, Switzerland (e-mail: [email protected]) Copyright © 2009 LLS SAS. All rights reserved 281 www.dialogues-cns.org PAGES_10_AG_019_BA.qxd:DCNS#42 30/08/09 1:25 Page 282 Translational research Selected abbreviations and acronyms strophic consequences for neurons. In the present review Aͱ amyloid-beta we discuss the intrinsically protective role of astrocytes AD Alzheimer’s disease in the normal brain, and examine how these defense GSH glutathione mechanisms may be overwhelmed in pathological con- MCT monocarboxylate transporter ditions, contributing to disease progression. ROS reactive oxygen species Astrocytes in the normal brain: modulate—changes in their microenvironment. Indeed, maintenance of extracellular homeostasis astrocytes can respond to neurotransmitters with tran- sient increases in their intracellular Ca2+ levels, which can Despite the fact that the brain has a very high metabolic travel through the astrocytic syncytium in a wavelike rate, neurons are by nature particularly sensitive to fashion.14,15 These Ca2+ signals can trigger the release of minute changes in their microenvironment. In this con- neuroactive molecules from astrocytes (or gliotransmit- text, neuronal function and viability would rapidly be ters), such as glutamate, D-serine, or adenosine triphos- compromised without effective mechanisms for the sup- phate (ATP) which in turn modulate synaptic activity ply of metabolic substrates and—equally as important— and neuronal excitability (see ref 16 for review). This for the removal of waste products. In this respect, astro- process, for which the term “gliotransmission” has been cytes play an essential role through a number of cellular coined, marks the emergence of an exciting new notion processes; some of the most important are outlined in that information processing may not be a unique feature the following section. of neurons. Remarkably, the phylogenetic evolution of the brain cor- relates with a steady increase of the astrocyte-to- neuron ratio—going from about 1/6 in nematodes to 1/3 in rodents, and reaching up to 1.65 astrocytes per neuron in the human cortex.3,17 Importantly, more than simply outnumbering their rodent counterparts, human astro- cytes are also strikingly more complex, both morpho- logically and functionally. In comparison, human neo- cortical astrocytes are 2.5 times larger, extend 10 times more processes, and display unique microanatomical features (Figure 1).2 In addition, they generate more robust intracellular Ca2+ responses to neurotransmitter receptor agonists and display a 4-fold increase in Ca2+ wave velocity.2 In light of these evolution-driven modi- fications, it is tempting to hypothesize that the astrocytic contribution to the overall neural network complexity may in part provide the fine tuning necessary to take information processing to a higher level of competence, such as that seen in humans. At the very least, the evo- lutionary pressure exerted on astrocytes highlights the importance of this glial cell type in sustaining normal Figure 1. Human astrocytes are more complex then their rodent coun- brain function as the brain itself becomes more complex. terparts. Typical human (A) and mouse (B) protoplasmic astro- A continuously growing body of evidence demonstrates cytes are shown at the same scale for comparison. Based on glial that astrocytes are essential sentinels and dynamic mod- fibrillary acidic protein (GFAP) immunostaining, human proto- plasmic astrocytes are 2.5-fold larger and project 10 times more ulators of neuronal function. Considering the strong main processes than mouse astrocytes. (GFAP, white. Scale bar, metabolic cooperation that exists between these two cell 20 µM). Adapted from ref 2: Oberheim NA, Takano T, Han X, et al. Uniquely types, it is not surprising that alterations in astrocytic hominid features of adult human astrocytes. J Neurosci. 2009;29:3276- function have been shown to have potentially cata- 3287. Copyright © Society for Neuroscience 2009 282 PAGES_10_AG_019_BA.qxd:DCNS#42 30/08/09 1:25 Page 283 Astroglia and neuroprotection - Bélanger and Magistretti Dialogues in Clinical Neuroscience - Vol 11 . No. 3 . 2009 Glutamate uptake and recycling synapse. Failure to do so would result in the rapid deple- tion of the glutamate pool in presynaptic neurons and Astrocytic processes surrounding synaptic elements subsequent disruption of excitatory neurotransmission. express transporters for a variety of neurotransmitters This transfer is achieved by the well-described gluta- and neuromodulators including glutamate, γ-aminobu- mate-glutamine cycle (Figure 2, pink box).27,28 In short, tyric acid (GABA), glycine, and histamine.5-8 These trans- glutamate is converted to glutamine by the astrocyte- porters participate in the rapid removal of neurotrans- specific enzyme glutamine synthetase (GS).29 Glutamine mitters released into the synaptic cleft, which is essential is then transferred to neurons in a process most likely for the termination of synaptic transmission and main- involving the amino acid transport systems N, L, and tenance of neuronal excitability. In the specific case of ASC in astrocytes and system A in neurons.27 Glutamine glutamate, its uptake by astrocytes is also crucial in pro- is then converted back to glutamate via deamination by tecting neurons against glutamate-induced excitotoxic- phosphate-activated glutaminase which is enriched in ity. Indeed, although glutamate is the primary excitatory the neuronal compartment. The ammonia produced in neurotransmitter in the brain, overstimulation of gluta- the process is thought to be shuttled back to astrocytes mate receptors is highly toxic to neurons (reviewed in following its incorporation into leucine and/or alanine.27 detail by Sattler and Tymianski).18 While basal extracel- It is important to note that glutamate can be metabo- lular glutamate levels are maintained in the low micro- lized in a number of different pathways in astrocytes and molar range, they increase dramatically during gluta- neurons, including oxidation in the tricarboxylic acid matergic neurotransmission, reaching up to 1 mM for a (TCA) cycle.28 Astrocytes are responsible for the replen- few milliseconds in the synaptic cleft.19