Astroglial plasticity and glutamate function in a chronic mouse model of Parkinson's disease.
Astrocytes play a major role in maintaining low levels of synaptically released glutamate, and in many neurodegenerative diseases, astrocytes become reactive and lose their ability to regulate glutamate levels, through a malfunction of the glial glutamate transporter-1. However, in Parkinson's disease, there are few data on these glial cells or their regulation of glutamate transport although glutamate cytotoxicity has been blamed for the morphological and functional decline of striatal neurons. In the present study, we use a chronic mouse model of Parkinson's disease to investigate astrocytes and their relationship to glutamate, its extracellular level, synaptic localization, and transport. C57/bl mice were treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p). From 4 to 8 weeks after treatment, these mice show a significant loss of dopaminergic terminals in the striatum and a significant increase in the size and number of GFAP-immunopositive astrocytes. However, no change in extracellular glutamate, its synaptic localization, or transport kinetics was detected. Nevertheless, the density of transporters per astrocyte is significantly reduced in the MPTP/p-treated mice when compared to controls. These results support reactive gliosis as a means of striatal compensation for dopamine loss. The reduction in transporter complement on individual cells, however, suggests that astrocytic function may be compromised. Although reactive astrocytes are important for maintaining homeostasis, changes in their ability to regulate glutamate and its associated synaptic functions could be important for the progressive nature of the pathophysiology associated with Parkinson's disease.
Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, USA.
Adrian G
AG
Dervan
Charles K
CK
Meshul
Mitchell
M
Beales
Gethin J
GJ
McBean
Cindy
C
Moore
Susan
S
Totterdell
Ann K
AK
Snyder
Gloria E
GE
Meredith
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001692:Biological Transport / Q000187:drug effects; D002452:Cell Count; D048429:Cell Size / Q000187:drug effects; D002908:Chronic Disease; D004195:Disease Models, Animal; D018450:Disease Progression; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D005911:Gliosis / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects / Q000473:pathology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D011339:Probenecid; D012964:Sodium / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000473:pathology
D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D018698:Glutamic Acid; D012964:Sodium; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D011339:Probenecid