title: Failure of axonal transport induces a spatially coincident increase in astrocyte BDNF prior to synapse loss in a central target.
abstract: 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.
authors.affiliation: The Vanderbilt Eye Institute, Vanderbilt University Medical Center, 11425 Langford Medical Research Building IV, 2213 Garland Avenue, Nashville, TN 37232, USA. scrish@neoucom.edu
authors.forename: S D
authors.initials: SD
authors.lastname: Crish
authors.forename: J D
authors.initials: JD
authors.lastname: Dapper
authors.forename: S E
authors.initials: SE
authors.lastname: MacNamee
authors.forename: P
authors.initials: P
authors.lastname: Balaram
authors.forename: T N
authors.initials: TN
authors.lastname: Sidorova
authors.forename: W S
authors.initials: WS
authors.lastname: Lambert
authors.forename: D J
authors.initials: DJ
authors.lastname: Calkins
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001370:Axonal Transport / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D004195:Disease Models, Animal; D005901:Glaucoma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009901:Optic Nerve Diseases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D013477:Superior Colliculi / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D014795:Visual Pathways / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger