CHAPTER 9
Astrocyte Signaling in
Neurological Disorders
A. R. JAYAKUMARab AND M. D. NORENBERG*abc
a Departments of Pathology, University of Miami School of Medicine, Miami, FL 33101, USA; b Veterans A airs Medical Center, Miami, FL 33125, USA; c Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, FL 33101, USA
9.1 Introduction
Astrocytes are neural (glial) cells with numerous functions in the central nervous system (CNS). Astrocytes become activated in response to CNS injury and undergo hypertrophy, a phenomenon referred to as reactive astrocytosis (astrogliosis). Whether this response is beneficial or detrimental remains controversial. Cell swelling is another common astrocytic response that contributes to brain edema and increased intracranial pressure in various neurological conditions. This chapter will review general features of these astrocytic responses and then discuss signaling mechanisms associated with these astrocytic alterations.
9.1.1Structure and Function of Astrocytes
9.1.1.1Morphology
Astrocytes are the most abundant cells in the central nervous system (CNS), and constitute about 30–50% of the mammalian brain volume, depending on
RSC Drug Discovery Series No. 10 Extracellular and Intracellular Signaling
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the brain region. Individual astrocytes possess non-overlapping domains,1,2 wherein in humans they associate with approximately 2,000,000 synapses.3 Astrocytes are, in a sense, the ‘‘epithelial’’ cells of the CNS in that they line key surfaces of the brain and spinal cord (subpial, subependymal, pericapillary and perisynaptic areas). Like epithelial cells they are enriched with gap junctions allowing them to communicate with adjacent astrocytes, resulting in a complex syncitium that encompass the entire CNS. This configuration allows them to interact with all major systems of the CNS, including neurons, other glial cells (microglia, oligodendrocytes) and capillaries.
Three major types of astrocytes are recognized in the CNS. Protoplasmic astrocytes are only found in grey matter, where they display numerous, highly branched, short cellular processes. Fibrous astrocytes are the dominant form in the white matter. These cells have sparsely branched but elongated cellular processes. Fibrous astrocytes are the cells that possess a star-like appearance (hence the term ‘‘astrocyte’’). Radial glial cells are generally observed only during development, where they assist neurons in their migration. Modified forms of astrocytes are present in the cerebellum (Bergmann glia) and Mu¨ller cells in the retina. The most commonly used marker for identifying astrocytes is the intermediate filament, glial fibrillary acidic protein (GFAP).
9.1.1.2Astrocyte Functions
While in the past astrocytes were traditionally viewed as only ‘‘supportive’’ cells, it is now clear that they play active and important roles in the CNS, including regulation of synaptogenesis,4,5 synaptic function,6,7 modulation of excitatory and inhibitory neurotransmission,8,9 pH and ion homoeostasis,10–12 regulation of energy metabolism13–15 and the detoxification of ammonia, metals and free
radicals.16–19 Astrocytes are also involved in the provision of nutrients to the neurons20 and formation and maintenance of the blood-brain barrier,21–23 assist
oligodendrocytes in the process of myelination,24–26 repair and scarring processes in CNS27,28 and also play a significant role in inflammation.29–31
Astrocytes are well known to release many trophic factors, including glial cell line-derived neurotrophic factor (GDNF),32,33 brain-derived neurotrophic factor (BDNF),32,33 vascular endothelial growth factor (VEGF),34,35 nerve growth factor (NGF),33 transforming growth factor beta (TGF-b),36,37 ciliary neurotrophic factor (CNTF),38 basic fibroblast growth factor (bFGF)39 and platelet-derived growth factor (PDGF).40 Astrocytes likewise secrete the nuclear protein high-mobility group box 1 (HMGB1), a cytokine-like factor that promotes inflammation, whose release has been shown to be protective against neuronal injury after ischemia.41,42
The glutamate-glutamine cycle is an important process in the regulation of the principal CNS neurotransmitters, glutamate and GABA. Under normal conditions, glutamate released from neurons is taken up by astrocytes and then converted into glutamine by the enzyme glutamine synthetase. Astrocytes then release glutamine, which is subsequently taken up by neurons and metabolized to glutamate by phosphate-activated glutaminase, and to GABA by glutamate