Failure of axonal transport induces a spatially coincident increase in astrocyte BDNF prior to synapse loss in a central target.

Crish SD, Dapper JD, MacNamee SE, Balaram P, Sidorova TN, Lambert WS, Calkins DJ
Neuroscience. 2013 229: 55-70

PMID: 23159315 · PMCID: PMC3534890 · DOI:10.1016/j.neuroscience.2012.10.069

Failure of anterograde transport to distal targets in the brain is a common feature of neurodegenerative diseases. We have demonstrated in rodent models of glaucoma, the most common optic neuropathy, early loss of anterograde transport along the retinal ganglion cell (RGC) projection to the superior colliculus (SC) is retinotopic and followed by a period of persistence of RGC axon terminals and synapses through unknown molecular pathways. Here we use the DBA/2J mouse model of hereditary glaucoma and an acute rat model to demonstrate that retinotopically focal transport deficits in the SC are accompanied by a spatially coincident increase in brain-derived neurotrophic factor (BDNF), especially in hypertrophic astrocytes. These neurochemical changes occur prior to loss of RGC synapses in the DBA/2J SC. In contrast to BDNF protein, levels of Bdnf mRNA decreased with transport failure, even as mRNA encoding synaptic structures remained unchanged. In situ hybridization signal for Bdnf mRNA was the strongest in SC neurons, and labeling for the immature precursor pro-BDNF was very limited. Subcellular fractionation of SC indicated that membrane-bound BDNF decreased with age in the DBA/2J, while BDNF released from vesicles remained high. These results suggest that in response to diminished axonal function, activated astrocytes in the brain may sequester mature BDNF released from target neurons to counter stressors that otherwise would challenge survival of projection synapses.

Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

MeSH Terms (14)

Animals Astrocytes Axonal Transport Brain-Derived Neurotrophic Factor Disease Models, Animal Glaucoma Mice Optic Nerve Diseases Rats Retinal Ganglion Cells RNA, Messenger Superior Colliculi Synapses Visual Pathways

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