Astrocyte Function and Role in Motor Neuron Disease: A Future Therapeutic Target? DANIEL BLACKBURN, * SIRANUSH SARGSYAN, PETER N. MONK, AND PAMELA J. SHAW Academic Neurology Unit, Sheffield Care and Research Centre for Motor Neuron Disorders, University of Sheffield, Sheffield, United Kingdom KEY WORDS astrocytes; astrogliosis; glial fibrillary acidic protein (GFAP); motor neuron disease (MND) ABSTRACT Astrocytes are the most numerous cell type within the cen- tral nervous system (CNS) and perform a variety of tasks, from axon guidance and synaptic support, to the control of the blood brain barrier and blood flow. To perform these roles, there is a great variety of astrocytes. In this review, we summarize the function of astrocytes, in particular, their role in maintaining homeostasis at the synapse, regu- lating neuronal signaling, protecting neurons from oxida- tive damage, and determining the fate of endogenous neu- ral precursors. The review also highlights recent develop- ments indicating the role of astrocytes in motor neuron disease (MND), emphasizing their potential as therapeutic targets and agents in cell replacement therapy. The Cu-Zn superoxide dismutase (SOD1) gene that has been impli- cated in 20% of cases of familial MND must be expressed in the glial cells as well as motor neurons to produce the dis- ease state in murine models of disease. Selectively reducing mutant SOD1 (mSOD1) in astrocytes does not affect disease onset but slows disease progression, whereas reducing mSOD1 in motor neurons delays disease onset and slows early disease but has less effect on life span. This suggests that glial cells represent potential therapeutic targets in MND. However, the lack of specific markers for astrocytes, their precursors, and sub-types means that our knowledge of astrocyte development/differentiation and response to injury lags far behind our understanding of function. Only by filling this knowledge gap can astrocytes be effectively targeted or replaced to successfully treat chronic CNS dis- orders such as MND. V V C 2009 Wiley-Liss, Inc., INTRODUCTION Over the last 2 decades, there has been increasing in- terest and research into astrocytes, the most abundant cell type within the central nervous system (CNS). Astrocytes do not just provide trophic, metabolic, and structural support for neurons, but play an active role in complex neuronal-glial communication, synaptic sig- naling, regulation of blood flow, and can strongly influ- ence neural precursors/stem cells in the adult CNS (Sei- fert et al., 2006). This multi-functionality may explain the multiplicity of astrocyte subtypes found throughout the CNS. The human CNS has the highest numbers of glia, the greatest glia-neuron ratio(Araque et al., 2001; Valverde and Lopez-Mascaraque, 1991) and the greatest heterogeneity of glial cells (Oberheim et al., 2006) com- pared with other animal species. In acute CNS injury, reactive astrocytes may initially be protective, but the resulting long-lived astroglial scar also prevents axonal regrowth. Thus, the proliferation of astrocytes, seen in neurodegenerative diseases such as motor neuron disease (MND) may have protective and harmful effects. Astrocytes are potential targets of drug and cell replacement therapies in acute and chronic motor neuron injury. However, there remains a paucity of specific markers for the sub-types of mature astro- cytes and their precursor cells that are needed to under- stand the local factors that determine the fate of special- ized astrocytes. Increasingly sophisticated methods to study the complex astrocyte-neuronal interaction (using acute slices and in-vivo imaging) along with transgenic technologies to investigate the origin and the fate of re- active astrocytes are now being used to determine whether reactive astrocytes can be manipulated to pro- mote a neuroprotective environment. This article will review some of the recent developments from these in vivo experiments which highlight the role of astrocytes in many of the key functions of the CNS. This review will also highlight the recent developments for the role of astrocytes in motor neuron disease (MND), emphasiz- ing their potential as therapeutic targets and agents in cell replacement therapy. IDENTIFICATION AND ORIGIN OF ASTROCYTES Antibodies to glial fibrillary acidic protein (GFAP) are the most commonly used tool to identify astrocytes. GFAP is a member of the intermediate filament (IF) superfamily and is present in lower amounts in proto- plasmic than in fibrous astrocytes and also labels epen- dymocytes, radial glial (RG) cells, nonmyelinating Grant sponsors: Wellcome Trust, Medical Research Council, Motor Neuron Dis- ease Association, University of Sheffield (Grave’s Fellowship), British Medical Association (Vera Down Award). *Correspondence to: Daniel Blackburn, Clinical Research Fellow, Academic Neurology Unit, Section of Neuroscience, E-Floor, Medical School, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, United Kingdom. E-mail: d.blackburn@sheffield.ac.uk Received 13 April 2008; Accepted 16 December 2008 DOI 10.1002/glia.20848 Published online 16 April 2009 in Wiley InterScience (www.interscience. wiley.com). GLIA 57:1251–1264 (2009) V V C 2009 Wiley-Liss, Inc.