Glucocorticoid regulation of glial responses during hippocampal neurodegeneration and regeneration.
Glucocorticoids can prevent or accelerate neurodegeneration in the adult rat hippocampus. To investigate these actions of glucocorticoids, we previously cloned genes from the hippocampus. Adrenalectomy specifically increased glial fibrillary acidic protein and transforming growth factor (TGF)-beta1 mRNAs in the dentate gyrus and these effects were dependent on induced apoptosis. Corticosterone treatment prevented apoptosis, and decreased glial activation and the influx of activated microglia. Since these effects are opposite to injury and neurodegeneration, we propose that they represent adaptive actions of glucocorticoids, preventing cellular defense mechanisms from overshooting. We used adrenalectomy as a model to investigate how adult granule neurons die in vivo and the effects of neurotrophic factors in protecting against apoptosis. Neurotrophin-4/5 and TGF-beta1 protected granule neurons against adrenalectomy-induced apoptosis. Since neurogenesis is also greatly increased in the dentate gyrus following adrenalectomy, we compared the time course of birth and death with glial responses. TGF-beta1 mRNA increased before the detection of dying cells in the dentate gyrus, which was coincident with increased proliferation in the neurogenic zone. Glucocorticoids also increased Ndrg2 mRNA in glia in the neurogenic zone; Ndrg2 is a member of a novel gene family involved in neural differentiation and synapse formation. Therefore, studying the effects of glucocorticoid manipulation on the dentate gyrus is increasing our understanding of how mature neurons die by apoptosis and the role of glia in induced apoptosis and neurogenesis. Discovering how endocrine and inflammatory responses regulate neuron birth and survival is important for developing successful neuron replacement strategies to treat neurodegenerative diseases.
Nichols
Nancy R
NR
Department of Physiology, Building 13F, Monash University, Clayton, Australia. nancy.nichols@med.monash.edu.au
Agolley
David
D
Zieba
Malgorzata
M
Bye
Nicole
N
D000315:Adrenalectomy / Q000379:methods; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D003001:Cloning, Molecular; D005786:Gene Expression Regulation / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D005938:Glucocorticoids / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D009416:Nerve Regeneration / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D005904:Glial Fibrillary Acidic Protein; D005938:Glucocorticoids; C466228:NDRG2 protein, human; D011506:Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins