Axogenic mechanism enhances retinal ganglion cell excitability during early progression in glaucoma

Risner, Michael L.; Pasini, Silvia; Cooper, Melissa; Lambert, Wendi S.; Calkins, David J.

doi:10.1073/pnas.1714888115

Cited by 102 publications

(170 citation statements)

References 51 publications

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“…The apparently independent effect of directly increasing perinuclear cAMP levels and KCl stimulation may simply reflect the quantitative ability of KCl to promote such elevations, because, for example, neurons rapidly desensitize to chronic KCl exposure. Axon damage induced by injury such as from increased intraocular pressure leads to enhanced RGC excitability that can temporarily delay degeneration (Risner et al, 2018). It has also been reported that intrinsically photosensitive retinal ganglion cells (ipRGCs) are more resistant to insult than other RGC subtypes because of their increased electrical excitability (Li et al, 2006;Daniel et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Neuronal Survival and Axon Growth by a Perinuclear cAMP Compartment

Boczek

Cameron

et al. 2019

J. Neurosci.

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cAMP signaling is known to be critical in neuronal survival and axon growth. Increasingly the subcellular compartmentation of cAMP signaling has been appreciated, but outside of dendritic synaptic regulation, few cAMP compartments have been defined in terms of molecular composition or function in neurons. Specificity in cAMP signaling is conferred in large part by A-kinase anchoring proteins (AKAPs) that localize protein kinase A and other signaling enzymes to discrete intracellular compartments. We now reveal that cAMP signaling within a perinuclear neuronal compartment organized by the large multivalent scaffold protein mAKAP␣ promotes neuronal survival and axon growth. mAKAP␣ signalosome function is explored using new molecular tools designed to specifically alter local cAMP levels as studied by live-cell FRET imaging. In addition, enhancement of mAKAP␣-associated cAMP signaling by isoform-specific displacement of bound phosphodiesterase is demonstrated to increase retinal ganglion cell survival in vivo in mice of both sexes following optic nerve crush injury. These findings define a novel neuronal compartment that confers cAMP regulation of neuroprotection and axon growth and that may be therapeutically targeted in disease. Significance StatementcAMP is a second messenger responsible for the regulation of diverse cellular processes including neuronal neurite extension and survival following injury. Signal transduction by cAMP is highly compartmentalized in large part because of the formation of discrete, localized multimolecular signaling complexes by A-kinase anchoring proteins. Although the concept of cAMP compartmentation is well established, the function and identity of these compartments remain poorly understood in neurons. In this study, we provide evidence for a neuronal perinuclear cAMP compartment organized by the scaffold protein mAKAP␣ that is necessary and sufficient for the induction of neurite outgrowth in vitro and for the survival of retinal ganglion cells in vivo following optic nerve injury.

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Section: Discussionmentioning

confidence: 99%

Regulation of Neuronal Survival and Axon Growth by a Perinuclear cAMP Compartment

Boczek

Cameron

et al. 2019

J. Neurosci.

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“…Notably, this occurred early in disease 483 progression; synaptic changes were not associated with detectable loss of the ChR2-expressing RGC 484 populations under study, although RGCs detected with a non-specific RGC marker were slightly reduced 485in the peripheral retina. These effects might therefore represent an early homeostatic responses to OHT-486 triggered effects on the optic nerve(Crish and Calkins, 2015;Risner et al, 2018). These novel findings 487 demonstrate an early-stage impact of elevated eye pressure of the sort that mimics human disease on the 488 function of the optic nerve and a key brain region receiving direct input from the retina and thereby shed 489light on a critical link between OHT and vision loss in glaucoma.490RGC axon damage at the optic nerve head is a key trigger for neurodegeneration in glaucoma and 491 axonopathy is a core component of numerous neurodegenerative diseases(Salvadores et al, 2017).…”

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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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“…In this study, we show that elevation of IOP via injection of microbeads into the anterior chamber, a widely used experimental model for glaucoma (Sappington et al, 2010; El-Danaf and Huberman, 2015; Pang et al, 2015; Risner et al, 2018), leads to upregulation of CP-AMPARs in RGCs. This form of AMPAR remodeling is cell-type specific, completely absent in α Off sustained RGCs, robust in α Off transient RGCs, and more modest in α On RGCs.…”

Section: Discussionmentioning

confidence: 74%

“…Several mouse models have been developed to induce IOP, including injection of microspheres which reduce aqueous outflow through the trabecular meshwork, causing a long lasting increase in ocular pressure (Sappington et al, 2010). Within one week following elevation of IOP, there are a number of morphological and functional changes in RGCs including axonal transport (Buckingham et al, 2008; Crish et al, 2010; Calkins, 2012; Ward et al, 2014), dendritic morphology (Della Santina et al, 2013; El-Danaf and Huberman, 2015), decreases in synaptic responses, the patterns of light-driven input to RGCs (Holcombe et al, 2008; Frankfort et al, 2013; Chen et al, 2015; El-Danaf and Huberman, 2015; Pang et al, 2015) and membrane excitability (Risner et al, 2018). However, it is currently unclear whether these previously described changes contribute directly to RGC death, or whether other yet to be described changes are critical.…”

Section: Introductionmentioning

confidence: 99%

Ocular hypertension drives remodeling of AMPA receptors in select populations of retinal ganglion cells

Sladek

Nawy

2019

Preprint

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148 words) 1 AMPA receptors in the CNS are normally impermeable to Ca 2+ but aberrant expression of 2 Ca 2+ -permeable AMPA receptors (CP-AMPARs) occurs in pathological conditions such as 3 ischemia or epilepsy, or in degenerative diseases such as ALS. Here we show that select 4 populations of retinal ganglion cells (RGCs) similarly express high levels of CP-AMPARs in 5 a mouse model of glaucoma. CP-AMPAR expression increased dramatically in both α On 6 and α transient Off RGCs, and this increase was prevented by genomic editing of the 7 GluA2 Q/R site. α On RGCs with elevated CP-AMPAR levels displayed profound synaptic 8 depression, which was reduced by selectively blocking CP-AMPARs, buffering Ca 2+ with 9 BAPTA, or with the CB1 antagonist AM251, suggesting that depression was mediated by a 10 retrograde transmitter which might be triggered by influx of Ca 2+ through CP-AMPARs.11 Thus OHT alters the composition of AMPARs and modulates patterns of synaptic activity 12 in select populations of RGCs. 13 14 27 CP-AMPARs, and decrease synaptic gain. We explore the possibility that CP-AMPAR 28 expression and synaptic gain are linked, with CP-AMPARs providing a route of Ca 2+ influx 29 to activate a retrograde messenger that reduces transmitter release from the presynaptic 30 bipolar cell.31 Results 32 5 α transient and sustained Off RGCs express predominantly Ca 2+ -impermeant

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Axogenic mechanism enhances retinal ganglion cell excitability during early progression in glaucoma

Cited by 102 publications

References 51 publications

Regulation of Neuronal Survival and Axon Growth by a Perinuclear cAMP Compartment

Regulation of Neuronal Survival and Axon Growth by a Perinuclear cAMP Compartment

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

Ocular hypertension drives remodeling of AMPA receptors in select populations of retinal ganglion cells

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