Abstract
Axonopathy is a hallmark of many neurodegenerative diseases including glaucoma, where elevated intraocular pressure (ocular hypertension, OHT) stresses retinal ganglion cell (RGC) axons as they exit the eye and form the optic nerve. OHT causes early changes in the optic nerve such as axon atrophy, transport inhibition, and gliosis. Importantly, many of these changes appear to occur prior to irreversible neuronal loss, making them promising points for early diagnosis of glaucoma. It is unknown whether OHT has similarly early effects on the function of RGC output to the brain. To test this possibility, we elevated eye pressure in mice by anterior chamber injection of polystyrene microbeads. Five weeks post-injection, bead-injected eyes showed a modest RGC loss in the peripheral retina, as evidenced by RBPMS antibody staining. Additionally, we observed reduced dendritic complexity and lower spontaneous spike rate of On-αRGCs, targeted for patch clamp recording and dye filling using a Opn4-Cre reporter mouse line. To determine the influence of OHT on retinal projections to the brain, we expressed Channelrhodopsin-2 (ChR2) in melanopsin-expressing RGCs by crossing the Opn4-Cre mouse line with a ChR2-reporter mouse line and recorded post-synaptic responses in thalamocortical relay neurons in the dorsal lateral geniculate nucleus (dLGN) of the thalamus evoked by stimulation with 460 nm light. The use of a Opn4-Cre reporter system allowed for expression of ChR2 in a narrow subset of RGCs responsible for image-forming vision in mice. Five weeks following OHT induction, paired pulse and high-frequency stimulus train experiments revealed that presynaptic vesicle release probability at retinogeniculate synapses was elevated. Additionally, miniature synaptic current frequency was slightly reduced in brain slices from OHT mice and proximal dendrites of post-synaptic dLGN relay neurons, assessed using a Sholl analysis, showed a reduced complexity. Strikingly, these changes occurred prior to major loss of RGCs labeled with the Opn4-Cre mouse, as indicated by immunofluorescence staining of ChR2-expressing retinal neurons. Thus, OHT leads to pre- and post-synaptic functional and structural changes at retinogeniculate synapses. Along with RGC dendritic remodeling and optic nerve transport changes, these retinogeniculate synaptic changes are among the earliest signs of glaucoma.
Highlights
Axonopathy is a common feature of many neurodegenerative diseases including glaucoma, a blinding disorder that leads to vision loss due to the degeneration of retinal ganglion cells (RGCs) and their projections to visual nuclei in the brain (Calkins, 2012; Weinreb et al, 2014)
While M1type melanopsin-expressing RGCs are well known for their role in circadian photoentrainment and pupillary constriction, these cells generally do not project to the dorsal lateral geniculate nucleus of the thalamus (dLGN)
Following counting of RGC somata, we found that RBPMS-stained RGC density was similar in all four quadrants of central retinas from control and
Summary
Axonopathy is a common feature of many neurodegenerative diseases including glaucoma, a blinding disorder that leads to vision loss due to the degeneration of retinal ganglion cells (RGCs) and their projections to visual nuclei in the brain (Calkins, 2012; Weinreb et al, 2014). In retinorecipient brain regions such as the superior colliculus (SC), suprachiasmatic nucleus (SCN), and dorsal lateral geniculate nucleus of the thalamus (dLGN), studies with post-mortem human tissue and animal models have shown that OHT and glaucoma eventually lead to glial activation, changes in neuronal structure, neuron loss, and atrophy of RGC axon terminals (Chaturvedi et al, 1993; Yücel et al, 2000, 2001, 2003, 2006; Gupta et al, 2006, 2007, 2009; Zhang et al, 2009; Crish et al, 2010; Ito et al, 2011; Ly et al, 2011; Calkins, 2012; Shimazawa et al, 2012; Wong and Brown, 2012; Liu et al, 2014; Chen et al, 2015; Yucel and Gupta, 2015; Smith et al, 2016)
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