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Altered astrocytic response to activation in SOD1 G93A mice and its implications on amyotrophic lateral sclerosis pathogenesis
Author(s) -
Benkler Chen,
BenZur Tali,
Barhum Yael,
Offen Daniel
Publication year - 2013
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.22428
Subject(s) - astrocyte , glutamatergic , amyotrophic lateral sclerosis , neurodegeneration , neuroscience , sod1 , excitotoxicity , glutamate receptor , biology , gliosis , neuroglia , motor neuron , neuroinflammation , central nervous system , medicine , immunology , inflammation , pathology , spinal cord , disease , biochemistry , receptor
Amyotrophic Lateral Sclerosis (ALS) is a fatal, rapidly progressive, neurodegenerative disease caused by motor neuron degeneration. Despite extensive efforts, the underlying cause of ALS and the path of neurodegeneration remain elusive. Astrocyte activation occurs in response to central nervous system (CNS) insult and is considered a double edged sword in many pathological conditions. We propose that reduced glutamatergic and trophic response of astrocytes to activation may, over time, lead to accumulative CNS damage, thus facilitating neurodegeneration. We found that astrocytes derived from the SOD1 G93A ALS mouse model exhibit a reduced glutamatergic and trophic response to specific activations compared to their wild‐type counterparts. Wild‐type astrocytes exhibited a robust response when activated with lipopolysaccharide (LPS), G5 or treated with ceftriaxone in many parameters evaluated. These parameters include increased expression of GLT‐1 and GLAST the two major astrocytic glutamate transporters, accompanied by a marked increase in the astrocytic glutamate clearance and up‐regulation of neurtrophic factor expression. However, not only do un‐treated SOD1 G93A astrocytes take up glutamate less efficiently, but in response to activation they show no further increase in any of the glutamatergic parameters evaluated. Furthermore, activation of wild‐type astrocytes, but not SOD1 G93A astrocytes, improved their ability to protect the motor neuron cell line NSC‐34 from glutamate induced excitotoxicity. Our data indicates that altered astrocyte activation may well be pivotal to the pathogenesis of ALS. © 2012 Wiley Periodicals, Inc.