GFAP knockout mice have increased levels of GDNF that protect striatal neurons from metabolic and excitotoxic insults.
In response to injury and degeneration, astrocytes hypertrophy, extend processes, and increase production of glial fibrillary acidic protein (GFAP), an intermediate filament protein located within their cytoplasm. The present study tested the hypothesis that GFAP expression alters the vulnerability of neurons to excitotoxic and metabolic insult induced by 3-nitroproprionic acid (3-NP), an irreversible inhibitor of mitochondrial complex II activity or the excitotoxin quinolinic acid (QA). In this respect, adult GFAP knockout mice (KO) and wild-type control mice (WT) received unilateral intrastriatal injections of 3-NP (200 nmol/microl) or QA (100 nmol/microl) and were killed 1, 2, or 4 weeks later. Lesion volume and neuronal counts were quantified using unbiased stereologic principles. For both QA and 3-NP lesions, a significant decrease in lesion volume and an increase in striatal projection neurons were seen in GFAP KO mice compared with WT mice. Enzyme-linked immunoassay analysis revealed increased basal levels of glial cell derived neurotrophic factor (GDNF) relative to WT mice. In contrast, no differences were observed in the expression of ciliary neurotrophic factor or nerve growth factor. These data strongly suggest that the expression of GFAP is implicated with the production of GDNF to a degree that confers neuroprotection after an excitotoxic or metabolic insult.
Research Center for Brain Repair and Department of Neurological Sciences, Rush Presbyterian Medical Center, Chicago, Illinois 60612, USA.
Rose
R
Hanbury
Zao Dung
ZD
Ling
Joanne
J
Wuu
Jeffrey H
JH
Kordower
D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000502:physiology; D020934:Ciliary Neurotrophic Factor / Q000032:analysis; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004797:Enzyme-Linked Immunosorbent Assay; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000032:analysis / Q000502:physiology*; D009419:Nerve Tissue Proteins; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000032:analysis / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D009574:Nitro Compounds; D010750:Phosphoproteins / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D017378:Quinolinic Acid / Q000494:pharmacology
D020934:Ciliary Neurotrophic Factor; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009574:Nitro Compounds; D010750:Phosphoproteins; D011422:Propionates; D017378:Quinolinic Acid; C015392:3-nitropropionic acid