Persistence of intact retinal ganglion cell terminals after axonal transport loss in the DBA/2J mouse model of glaucoma

Smith, Matthew A.; Xia, Christina Z.; Fening, Kelly M.; Inman, Denise M.; Schofield, Brett R.; Crish, Samuel D.

doi:10.1002/cne.24012

Cited by 24 publications

(42 citation statements)

References 97 publications

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“…In our sample of 9m D2 mice, we found that RGC axon terminals were lost in an IOP-dependent manner. We did not see evidence of either RGC axon terminal atrophy or swelling, as has been reported in ultrastructural studies of the SC (Smith et al, 2016). Several possibilities could account for this difference.…”

Section: Discussionsupporting

confidence: 69%

“…Prior studies have indicated that RGC axon terminals in the superior colliculus (SC) are lost fairly late in disease in DBA/2J and microbead-injected mice and that terminal loss is preceded by swelling followed by atrophy (Crish et al, 2010; Smith et al, 2016). Additionally, we have shown that five weeks of a relatively modest and sustained OHT triggered by anterior chamber microbead injections does not have any effect on RGC axon terminal size or density in the dLGN (Bhandari et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies of the superior colliculus of D2 mice have reported that RGC axon terminals survive until fairly late in the disease and only degenerate well after RGC loss (Crish et al, 2010; Smith et al, 2016; Wilson et al, 2016). In our sample of 9m D2 mice, we found that RGC axon terminals were lost in an IOP-dependent manner.…”

Section: Discussionmentioning

confidence: 96%

“…Within the retina, for instance, pressure elevation upregulates Na + channel expression and spiking behavior of RGCs, alters the size and complexity of their dendritic fields, changes receptive field properties, leads to changes in post-synaptic receptor composition, and alters the responses of upstream retinal circuits (Della Santina et al, 2013, 2013; Frankfort et al, 2013; Wang et al, 2014; Pang et al, 2015; Ou et al, 2016; Bhandari et al, 2019; McGrady et al, 2020; Sladek and Nawy, 2020). Within the optic projection and at RGC output sites in the brain, eye pressure and glaucomatous injury lead to alterations in optic nerve glial function and energy demands (Baltan et al, 2010; Inman and Harun-Or-Rashid, 2017; Jassim et al, 2019; Cooper et al, 2020), RGC axon terminal swelling and atrophy (Smith et al, 2016), changes in axon terminal mitochondrial health (Smith et al, 2016), altered synaptic vesicle release properties (Bhandari et al, 2019), and post-synaptic neuronal dendritic remodeling and somatic atrophy (Gupta and Yücel, 2003; Gupta et al, 2007, 2009, Liu et al, 2011, 2014; Bhandari et al, 2019). It is likely that such changes represent a mix of both homeostatic attempts at preserving retinal output fidelity and pathological alterations in neural function in glaucoma.…”

Section: Introductionmentioning

confidence: 99%

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Neuronal and synaptic plasticity in the visual thalamus in mouse models of glaucoma

Hook

Monaco

SMITH

2020

Preprint

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Homeostatic plasticity plays important roles in regulating synaptic and intrinsic neuronal function to stabilize output following perturbations to circuit activity. In glaucoma, a neurodegenerative disease of the visual system commonly associated with elevated intraocular pressure (IOP), early disease is associated with altered synaptic inputs to retinal ganglion cells (RGCs), changes in RGC intrinsic excitability, and deficits in optic nerve transport and energy metabolism. These early functional changes can precede RGC degeneration and are likely to alter RGC outputs to their target structures in the brain and thereby trigger homeostatic changes in synaptic and neuronal properties in those brain regions. In this study, we sought to determine whether and how neuronal and synaptic function is altered in the dorsal lateral geniculate nucleus (dLGN), an important RGC projection target in the thalamus, and how functional changes relate to IOP. We accomplished this using patch-clamp recordings from thalamocortical (TC) relay neurons in the dLGN in two established mouse models of glaucoma - the DBA/2J (D2) genetic mouse model and an inducible glaucoma model with intracameral microbead injections to elevate IOP. We found that the intrinsic excitability of TC neurons was enhanced in D2 mice and these functional changes were mirrored in recordings of TC neurons from microbead-injected mice. Notably, many neuronal properties were correlated with IOP in older D2 mice, but not younger D2 mice or microbead-injected mice. The frequency of miniature excitatory synaptic currents (mEPSCs) was reduced in both ages of D2 mice, and vGlut2 staining of RGC synaptic terminals was reduced in an IOP-dependent manner in older D2 mice. Among D2 mice, functional changes observed in younger mice without elevated IOP were distinct from those observed in older mice with elevated IOP and RGC degeneration, suggesting that glaucoma-associated changes to neurons in the dLGN might represent a combination of stabilizing/homeostatic plasticity at earlier stages and pathological dysfunction at later stages.

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Section: Discussionsupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Neuronal and synaptic plasticity in the visual thalamus in mouse models of glaucoma

Hook

Monaco

SMITH

2020

Preprint

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“…Prior studies have suggested that RGC axon terminals in the dLGN and superior colliculus persist 418 fairly late into disease in rodent glaucoma models Smith et al, 2016). However, to test 419 whether this reduction in mEPSC frequency might be due to the loss or atrophy of RGC axon terminals, 420…”

mentioning

confidence: 99%

Early-Stage Ocular Hypertension Alters Retinal Ganglion Cell Synaptic Transmission in the Visual Thalamus

Bhandari

SMITH

Zhang

et al. 2019

Preprint

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27Axonopathy is a hallmark of many neurodegenerative diseases including glaucoma, where elevated 28 intraocular pressure (ocular hypertension, OHT) stresses retinal ganglion cell (RGC) axons as they exit 29 the eye and form the optic nerve. OHT causes early changes in the optic nerve such as axon atrophy, 30 transport inhibition, and gliosis. Importantly, many of these changes appear to occur prior to irreversible 31 neuronal loss, making them promising points for early diagnosis of glaucoma. It is unknown whether 32OHT has similarly early effects on the function of RGC output to the brain. To test this possibility, we 33 elevated eye pressure in mice by anterior chamber injection of polystyrene microbeads. 5 weeks post-34injection, bead-injected eyes showed a modest RGC loss in the peripheral retina, as evidenced by RBPMS 35 antibody staining. Additionally, we observed reduced dendritic complexity and lower spontaneous spike 36 rate of On-RGCs, targeted for patch clamp recording and dye filling using a Opn4-cre reporter mouse 37 line. To determine the influence of OHT on retinal projections to the brain, we expressed 38Channelrhodopsin-2 (ChR2) in melanopsin-expressing retinal ganglion cells by crossing the Opn4-cre 39 mouse line with a ChR2-reporter mouse line and recorded post-synaptic responses in thalamocortical 40relay neurons in the dorsal lateral geniculate nucleus (dLGN) of the thalamus evoked by stimulation with 41 460 nm light. The use of a Opn4-cre reporter system allowed for expression of ChR2 in a narrow subset 42of RGCs responsible for image-forming vision in mice. Five weeks following OHT induction, paired 43 pulse and high-frequency stimulus train experiments revealed that presynaptic vesicle release probability 44at retinogeniculate synapses was elevated. Additionally, miniature synaptic current frequency was slightly 45 reduced in brain slices from OHT mice and proximal dendrites of post-synaptic dLGN relay neurons, 46assessed using a Sholl analysis, showed a reduced complexity. Strikingly, these changes occurred prior to 47 major loss of RGCs labeled with the Opn4-Cre mouse, as indicated by immunofluorescence staining of 48ChR2-expressing retinal neurons. Thus, OHT leads to pre-and post-synaptic functional and structural 49 changes at retinogeniculate synapses. Along with RGC dendritic remodeling and optic nerve transport 50 changes, these retinogeniculate synaptic changes are among the earliest signs of glaucoma. 51 52

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Anterograde Tract Tracing for Assaying Axonopathy and Transport Deficits in Glaucoma

Crish

Schofield

2017

Glaucoma

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Whether to stage degeneration or investigate early pathology in glaucoma, examination of axonal structure and function is essential. There are a wide variety of methods available to investigators using animal models of glaucoma, with varying utilities depending on the questions asked. Here, we describe the use of anterograde neuronal tract tracing using cholera toxin B (CTB) for the determination of axon transport integrity of the retinofugal projection. This method reveals the structure of the retinal axons as well as the functional integrity of anterograde transport systems.

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Persistence of intact retinal ganglion cell terminals after axonal transport loss in the DBA/2J mouse model of glaucoma

Cited by 24 publications

References 97 publications

Neuronal and synaptic plasticity in the visual thalamus in mouse models of glaucoma

Neuronal and synaptic plasticity in the visual thalamus in mouse models of glaucoma

Early-Stage Ocular Hypertension Alters Retinal Ganglion Cell Synaptic Transmission in the Visual Thalamus

Anterograde Tract Tracing for Assaying Axonopathy and Transport Deficits in Glaucoma

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