Return of function after CNS axon regeneration: Lessons from injury-responsive intrinsically photosensitive and alpha retinal ganglion cells

Berry, Martin; Ahmed, Zubair; Logan, Ann

doi:10.1016/j.preteyeres.2018.11.006

Cited by 21 publications

(21 citation statements)

References 150 publications

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“…[46][47][48] Other studies have reported that aRGCs and ipRGCs are tolerant to optic nerve injury, and one explanation for this may be their high mTOR activity. 11,18,49,50 Therefore, future studies may focus on identifying the survival mechanisms in these two RGC subtypes. Furthermore, overexpression of OPN or melanopsin in RGCs boosts mTOR signaling to promote axon regeneration.…”

Section: Discussionmentioning

confidence: 99%

Survival of Alpha and Intrinsically Photosensitive Retinal Ganglion Cells in NMDA-Induced Neurotoxicity and a Mouse Model of Normal Tension Glaucoma

Honda

Namekata

Kimura

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. We assess if a retinal ganglion cells (aRGCs) and intrinsically photosensitive retinal ganglion cells (ipRGCs) survive in mouse models of glaucoma. METHODS. Two microliters of N-methyl-D-aspartate (NMDA; 1 mM) or PBS were injected intraocularly 7 days before sacrifice. Immunohistochemical analyses of the retina were performed using antibodies against RNA-binding protein with multiple splicing (RBPMS), osteopontin, and melanopsin. Immunohistochemical analyses also were performed in adult mice with glutamate/aspartate transporter (GLAST) deletion (GLAST knockout [KO] mice), a mouse model of normal tension glaucoma. RESULTS. NMDA-induced loss of RBPMS-positive total RGCs was 58.4% 6 0.4% compared to PBS-treated controls, whereas the loss of osteopontin-positive aRGCs was 5.0% 6 0.6% and that of melanopsin-positive ipRGCs was 7.6% 6 1.6%. In GLAST KO mice, the loss of total RGCs was 48.4% 6 0.9% compared to wild-type mice, whereas the loss of aRGCs and ipRGCs was 3.9% 6 0.4% and 9.3% 6 0.5%, respectively. The distribution of survived total RGCs, aRGCs, and ipRGCs was similar regardless of the location of the retina. CONCLUSIONS. These results suggest that aRGC and ipRGC are highly tolerant to NMDA-induced neurotoxicity and NTG-like neurodegeneration in GLAST KO mice.

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Section: Discussionmentioning

confidence: 99%

Survival of Alpha and Intrinsically Photosensitive Retinal Ganglion Cells in NMDA-Induced Neurotoxicity and a Mouse Model of Normal Tension Glaucoma

Honda

Namekata

Kimura

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…An even larger effect can be achieved when the PI3K/AKT/ mTOR pathway is activated by deleting Phosphatase and Tensin homolog (PTEN) or Tuberous Sclerosis Complex 1 (TSC1) (Park et al, 2008;de Lima et al, 2012). However, the number of RGCs responding to these treatments is small, less than 10% of the total RGCs in the retina (Duan et al, 2015;Berry et al, 2018). In addition, overactivation of the mTOR pathway by PTEN deletion causes undesired secondary effects such as an increase in RGC size (Duan et al, 2015) and even cancer (Xie et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

HDAC5 promotes optic nerve regeneration by activating the mTOR pathway

Pita-Thomas

Mahar

Joshi

et al. 2019

Experimental Neurology

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Neurons in the central nervous system (CNS) regenerate poorly compared to their counterparts in the peripheral nervous system. We previously showed that, in peripheral sensory neurons, nuclear HDAC5 inhibits the expression of regenerative associated genes. After nerve injury, HDAC5 is exported to the cytoplasm to promote axon regeneration. Here we investigated the role of HDAC5 in retinal ganglion cells (RGC), a CNS neuron which fails to survive and regenerate axons after injury. In contrast to PNS neurons, we found that HDAC5 is mostly cytoplasmic in naïve RGCs and its localization is not affected by optic nerve injury, suggesting that HDAC5 does not directly suppress regenerative associated genes in these cells. Manipulation of the PKCμ pathway, the canonical pathway that regulates HDAC5 localization in PNS neurons by phosphorylating serine 259 and 498, and other pathways that regulate nuclear/cytoplasmic transport did not affect HDAC5 cytoplasmic localization in RGC. Also, an HDAC5 mutant whose serine 259 and 488 were replaced by alanine (HDAC5 AA) to prevent phosphorylation and nuclear export showed a predominantly cytoplasmic localization, suggesting that HDAC5 resides mostly in the cytoplasm in RGCs. Interestingly, expression of HDAC5 AA , but not HDAC5 wild type, in RGCs in vivo

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“…Six subtypes of ipRGCs have been described to express at least small amounts of melanopsin (also known as Opn4), and are named M1-M6 [31,32]. Antibodies against melanopsin allow the identification of the large majority of ipRGCs, preferentially M1–M3, because M4 (which corresponds to the ON αRGC subtype [33,34]), M5 [35], and M6 [32] express less Opn4 than M1–M3 and are difficult to identify with standard immunohistochemistry [31,32,36,37,38,39,40]. In rats, the population of m + RGCs constitute approximately 2.5 and 2.7% of the pigmented and albino RGC populations, respectively [13,14,19,41,42].…”

Section: Introductionmentioning

confidence: 99%

Melanopsin+RGCs Are fully Resistant to NMDA-Induced Excitotoxicity

Vidal‐Villegas

Pierdomenico

Imperial-Ollero

et al. 2019

IJMS

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We studied short- and long-term effects of intravitreal injection of N-methyl-d-aspartate (NMDA) on melanopsin-containing (m+) and non-melanopsin-containing (Brn3a+) retinal ganglion cells (RGCs). In adult SD-rats, the left eye received a single intravitreal injection of 5µL of 100nM NMDA. At 3 and 15 months, retinal thickness was measured in vivo using Spectral Domain-Optical Coherence Tomography (SD-OCT). Ex vivo analyses were done at 3, 7, or 14 days or 15 months after damage. Whole-mounted retinas were immunolabelled for brain-specific homeobox/POU domain protein 3A (Brn3a) and melanopsin (m), the total number of Brn3a+RGCs and m+RGCs were quantified, and their topography represented. In control retinas, the mean total numbers of Brn3a+RGCs and m+RGCs were 78,903 ± 3572 and 2358 ± 144 (mean ± SD; n = 10), respectively. In the NMDA injected retinas, Brn3a+RGCs numbers diminished to 49%, 28%, 24%, and 19%, at 3, 7, 14 days, and 15 months, respectively. There was no further loss between 7 days and 15 months. The number of immunoidentified m+RGCs decreased significantly at 3 days, recovered between 3 and 7 days, and were back to normal thereafter. OCT measurements revealed a significant thinning of the left retinas at 3 and 15 months. Intravitreal injections of NMDA induced within a week a rapid loss of 72% of Brn3a+RGCs, a transient downregulation of melanopsin expression (but not m+RGC death), and a thinning of the inner retinal layers.

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Return of function after CNS axon regeneration: Lessons from injury-responsive intrinsically photosensitive and alpha retinal ganglion cells

Cited by 21 publications

References 150 publications

Survival of Alpha and Intrinsically Photosensitive Retinal Ganglion Cells in NMDA-Induced Neurotoxicity and a Mouse Model of Normal Tension Glaucoma

Survival of Alpha and Intrinsically Photosensitive Retinal Ganglion Cells in NMDA-Induced Neurotoxicity and a Mouse Model of Normal Tension Glaucoma

HDAC5 promotes optic nerve regeneration by activating the mTOR pathway

Melanopsin+RGCs Are fully Resistant to NMDA-Induced Excitotoxicity

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