Molecular, anatomical and functional changes in the retinal ganglion cells after optic nerve crush in mice

Yukita, Masayoshi; Machida, Shigeki; Nishiguchi, Koji M.; Tsuda, S.; Yokoyama, Yû; Yasuda, Masayuki; Maruyama, Kouichi; Nakazawa, Toru

doi:10.1007/s10633-014-9478-2

Cited by 21 publications

(18 citation statements)

References 24 publications

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“…Consistent with reports from other groups, 42,49,50 ONC resulted in a significant reduction of pSTR amplitudes in vehicle-treated mice at 7 days after axonal injury. However, this reduction was significantly attenuated by AMG487 treatment ( Figure 5, B and C).…”

Section: Pharmacological Blockade Of Cxcr3 Partially Prevents Rgc Dyssupporting

confidence: 91%

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Liu

Zhu

et al. 2017

The American Journal of Pathology

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Traumatic optic neuropathy (TON) is an acute injury of the optic nerve secondary to trauma. Loss of retinal ganglion cells (RGCs) is a key pathological process in TON, yet mechanisms responsible for RGC death remain unclear. In a mouse model of TON, real-time noninvasive imaging revealed a dramatic increase in leukocyte rolling and adhesion in veins near the optic nerve (ON) head at 9 hours after ON injury. Although RGC dysfunction and loss were not detected at 24 hours after injury, massive leukocyte infiltration was observed in the superficial retina. These cells were identified as T cells, microglia/monocytes, and neutrophils but not B cells. CXCL10 is a chemokine that recruits leukocytes after binding to its receptor C-X-C chemokine receptor (CXCR) 3. The levels of CXCL10 and CXCR3 were markedly elevated in TON, and up-regulation of CXCL10 was mediated by STAT1/3. Deleting CXCR3 in leukocytes significantly reduced leukocyte recruitment, and prevented RGC death at 7 days after ON injury. Treatment with CXCR3 antagonist attenuated TON-induced RGC dysfunction and cell loss. In vitro co-culture of primary RGCs with leukocytes resulted in increased RGC apoptosis, which was exaggerated in the presence of CXCL10. These results indicate that leukocyte recruitment in retinal vessels near the ON head is an early event in TON and the CXCL10/CXCR3 axis has a critical role in recruiting leukocytes and inducing RGC death. (Am J Pathol 2017, 187: 352e365; http://dx

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Section: Pharmacological Blockade Of Cxcr3 Partially Prevents Rgc Dyssupporting

confidence: 91%

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Liu

Zhu

et al. 2017

The American Journal of Pathology

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“…Comparing RGC numbers to function can be difficult as certain RGC phenotypic markers are more intimately linked to dysfunction than others. For example, whereas RBPMS is strongly associated with functional and dysfunction RGC alike(Rodriguez et al, 2014), Brn3a down-regulates following injury, even preceding the reduction in pSTR amplitude and thus presumably marks the early stages of RGC dysfunction(Yukita et al, 2015). Neuroprotection of RGC does not reverse RGC dysfunction, particularly if the IOP is still raised(Mead et al, 2016).…”

Section: Functional Assessmentsmentioning

confidence: 99%

Evaluating retinal ganglion cell loss and dysfunction

Mead

Tomarev

2016

Experimental Eye Research

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Retinal ganglion cells (RGC) bear the sole responsibility of propagating visual stimuli to the brain. Their axons, which make up the optic nerve, project from the retina to the brain through the lamina cribrosa and in rodents, decussate almost entirely at the optic chiasm before synapsing at the superior colliculus. For many traumatic and degenerative ocular conditions, the dysfunction and/or loss of RGC is the primary determinant of visual loss and are the measurable endpoints in current research into experimental therapies. To actually measure these endpoints in rodent models, techniques must ascertain both the quantity of surviving RGC and their functional capacity. Quantification techniques include phenotypic markers of RGC, retrogradely transported fluorophores and morphological measurements of retinal thickness whereas functional assessments include electroretinography (flash and pattern) and visual evoked potential. The importance of the accuracy and reliability of these techniques cannot be understated, nor can the relationship between RGC death and dysfunction. The existence of up to 30 types of RGC complicates the measuring process, particularly as these may respond differently to disease and treatment. Since the above techniques may selectively identify and ignore particular subpopulations, their appropriateness as measures of RGC survival and function may be further limited. This review discusses the above techniques in the context of their subtype specificity.

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“…In summary, 1) Optic nerve transection/crush resulting in selective RGC loss invariably cause dramatic loss of PERG signal in cats (Maffei and Fiorentini, 1981; Weber et al, 2008) monkeys (Gianfranceschi et al, 1999) rats(Berardi et al, 1990) and mice (Miura et al, 2009; Porciatti et al, 1996; Xia et al, 2014); pSTR and nSTR appear to be reduced in rats (Bui and Fortune, 2004) and mice (Liu et al, 2014; Smith et al, 2014; Yukita et al, 2015), but relatively less than the PERG (Liu et al, 2014); PhNR, OPs do not seem to be reduced in rats and mice (Li et al, 2005; Liu et al, 2014; Smith et al, 2014); in monkeys, retrograde RGC degeneration modestly alters the mfERG, and mfERG alterations are species-dependent (Nork et al, 2010), 2) Several pharmacological studies have demonstrated that interfering in various ways with activity of inner retina neurons reduces PERG as well as innerretina-sensitive ERG components in cats, rodents and primates(Bui and Fortune, 2004; Hare and Ton, 2002; Hood et al, 1999; Viswanathan et al, 2000). Interestingly, both spiking and non-spiking electrical activity contributes to the PERG and inner-retina-sensitive ERG components (Luo and Frishman, 2011; Miura et al, 2009; Trimarchi et al, 1990) (Harrison et al, 2006; Viswanathan et al, 2000), 3) Intraretinal recordings have demonstrated an inner retina origin for the PERG distinct from ERG b-wave (Baker et al, 1988; Sieving and Steinberg, 1987), 4) In the mouse, the bioelectrical field generated by the PERG is different from that of the Flash-ERG, and it is consistent with generators localized in the optic nerve head (Chou and Porciatti, 2012), 5) Functional retrograde transport of target-derived factors is necessary for PERG generation, as blocking axon transport in the optic nerve Chou (Chou et al, 2013) or lesioning the superior colliculus (Yang et al, 2013) impairs the PERG in the mouse.…”

Section: Introductionmentioning

confidence: 98%

Electrophysiological assessment of retinal ganglion cell function

Porciatti

2015

Experimental Eye Research

163

137

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The function of retinal ganglion cells (RGCs) can be non-invasively assessed in experimental and genetic models of glaucoma by means of variants of the ERG technique that emphasize the activity of inner retina neurons. The best understood technique is the Pattern Electroretinogram (PERG) in response to contrast-reversing gratings or checkerboards, which selectively depends on the presence of functional RGCs. In glaucoma models, the PERG can be altered before histological loss of RGCs; PERG alterations may be either reversed with moderate IOP lowering or exacerbated with moderate IOP elevation. Under particular luminance-stimulus conditions, the Flash-ERG displays components that may reflect electrical activity originating in the proximal retina and be altered in some experimental glaucoma models (positive Scotopic Threshold response, pSTR; negative Scotopic Threshold Response, nSTR; Photopic Negative Response, PhNR; Oscillatory Potentials, OPs; multifocal ERG, mfERG). It is not yet known which of these components is most sensitive to glaucomatous damage. Electrophysiological assessment of RGC function appears to be a necessary outcome measure in experimental glaucoma models, which complements structural assessment and may even predict it. Neuroprotective strategies could be tested based on enhancement of baseline electrophysiological function that results in improved RGC survival. The use of electrophysiology in glaucoma models may be facilitated by specifically designed instruments that allow high throughput, robust assessment of electrophysiological function.

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Molecular, anatomical and functional changes in the retinal ganglion cells after optic nerve crush in mice

Abstract: Decrease in pSTR likely reflected the early loss of RGC function after ONC and that declining expression of RGC-specific genes preceded anatomical and functional changes in the RGCs.

Cited by 21 publications

References 24 publications

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Evaluating retinal ganglion cell loss and dysfunction

Electrophysiological assessment of retinal ganglion cell function

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