Failure of axonal transport induces a spatially coincident increase in astrocyte BDNF prior to synapse loss in a central target
Highlights
► Glaucoma involves degeneration of the retinal ganglion cell projection. ► Deficits in retinal axon transport to the superior colliculus (SC) are retinotopic. ► BDNF increases retinotopically in the SC with transport loss prior to synapse loss. ► Astrocytes become hypertrophic in the transport lesion. ► Astrocytes may sequester BDNF for focal re-release.
Introduction
Most neurodegenerative disorders involve early signs of axonal dysfunction, including diminished active transport to and from major projection targets in the brain (Adalbert et al., 2009, Morfini et al., 2009). The same is so of the optic neuropathies, the most common of which is glaucoma. Glaucoma is the leading cause of irreversible blindness worldwide and is characterized by progressive degeneration of the retinal ganglion cell (RGC) projection to the brain (Nickells, 1996, Quigley, 1999, Quigley and Broman, 2006, Kwon et al., 2009, Susanna, 2009, Crish and Calkins, 2011). Age and sensitivity to intraocular pressure (IOP) are important risk factors for the disease (Gordon et al., 2002), so animal models that incorporate these are most useful.
The DBA/2J inbred mouse model of hereditary glaucoma presents age-dependent variations in IOP due to mutations that affect fluid flow in the anterior eye (Danias et al., 2003, Schuettauf et al., 2004, Jakobs et al., 2005, Zhou et al., 2005, Inman et al., 2006, Howell et al., 2007). Failure of axonal transport is among the earliest events in the DBA/2J, preceding both degeneration in the optic nerve and RGC somatic loss in the retina (Buckingham et al., 2008, Chidlow et al., 2011, Calkins, 2012). Deficits in anterograde transport from the retina appear earliest at the most distal RGC projection site in the superior colliculus (SC) and progress to more anterior sites over time (Crish et al., 2010). The SC is the primary target for RGC axons in the rodent brain (Hofbauer and Drager, 1985), and a robust complement of RGC axon terminals and their post-synaptic neurons persist there long after transport is completely depleted, which we have described quantitatively (Crish et al., 2010).
Both in the DBA/2J and an inducible model, deficits in anterograde transport progress from one retinotopic sector of the SC to the next (Crish et al., 2010), much like the progression of vision loss in human glaucoma (Goldblum and Mittag, 2002). Age is the predominant determinant of transport depletion, with elevated IOP as an additional stressor that biases the system toward dysfunction (Crish et al., 2010). The sectorial pattern of transport loss in the SC is similar to markers for RGC somatic and axonal pathology in animal models and to topographical loss of RGCs in human glaucomatous retinas (Jakobs et al., 2005, Schlamp et al., 2006, Reichstein et al., 2007, Lei et al., 2009).
Interestingly, we found that even well after axonal transport to the SC is completely depleted, key synaptic structures in the RGC projection persist (Crish et al., 2010). Neural targets in the brain respond to degenerative stressors like diminished transport with mechanisms thought to aid in the retention and/or recovery of afferent input that may include remodeling to compensate for loss (Kimura et al., 2006, Endo et al., 2007, Hennigan et al., 2007, Song et al., 2008). For example, after NMDA-induced excitotoxic RGC loss, both brain-derived neurotrophic factor (BDNF) and the astrocytic marker glial fibrillary acidic protein (GFAP) increase within the retinal recipient zone of the SC (Tanaka et al., 2009). Increases in target site BDNF may occur prior to overt degeneration in Alzheimer’s disease (Kimura et al., 2004), leading us to question if a similar mechanism is at play within the SC in response to transport failure induced by glaucomatous injury.
Section snippets
Animals
DBA/2J and its transgenic control strain D2-Gpnmb+ (Howell et al., 2007) were obtained along with C57BL/6 mice from Jackson Laboratories (Bar Harbor, ME, USA). All experimental procedures were approved by The Vanderbilt University Medical Center Institutional Animal Care and Use Committee. Animals were maintained in a 12-h light–dark cycle with standard rodent chow available ad libitum. We measured IOP in a subset of DBA/2 mice up to 10 months of age using the Tono-Pen XL (Medtronic Solan,
Focal increases in BDNF with transport loss
Previously we demonstrated that deficits in anterograde transport to the DBA/2J SC progress in retinotopic sectors and increase in likelihood and severity with age; age-dependent elevation in IOP is an additional stressor but not the primary predictor (Crish et al., 2010). The SC from the C57BL/6 (C57) and D2-Gpnmb+ non-glaucomatous mouse strains and a 3-month DBA/2J exhibited intact CTB signal across the sSC (Fig. 1A). This is reflected in the complete retinotopic representation of CTB signal
Discussion
The SC is the primary target for RGC axons in rodents, forming a complete and highly regular retinotopic representation of visual space (Hofbauer and Drager, 1985). Both in the DBA/2J and an inducible model of glaucoma (microbead occlusion), deficits in axonal transport to the SC progress retinotopically, like vision loss in glaucoma, and precede outright degeneration of the retinal projection (Buckingham et al., 2008, Crish et al., 2010). Age is the primary stressor associated with transport
Conclusions
Secondary degeneration of target sites in the brain is generally thought to be either concurrent with or just subsequent to the loss of primary input. We have shown using models of glaucoma that focal deficits in anterograde axonal transport from the retina to the SC induce a concurrent elevation of BDNF, especially in hypertrophic astrocytes, that is spatially coincident with the retinotopic location of transport loss. This elevation may reflect a local intrinsic pathway to slow loss of
Role of the funding source
Supported by NIH EY017427 (DJC), the Melza M. and Frank Theodore Barr Foundation through the Glaucoma Research Foundation (DJC), a Departmental Unrestricted Award from Research to Prevent Blindness, Inc. (DJC), an American Health Assistance Foundation National Glaucoma Research Award (DJC), Fight for Sight (SDC), the Vanderbilt Discovery Science program (DJC), and Vanderbilt Vision Research Center (P30EY008126).
Conflict of interest
The authors have no conflicts of interest to disclose.
Acknowledgments
We thank Mrs. Ann Gearon and Mr. Brian J. Carlson for their assistance with intraocular pressure measurements.
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Present address: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
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Present address: St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
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Present address: University of Arizona, Graduate Program in Neuroscience, 1548 E. Drachman St., P.O. Box 210476, Tucson, AZ 85721, USA.
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Present address: Department of Psychology and Vanderbilt Vision Research Center, Vanderbilt University, Nashville, TN 37203, USA.