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BioRxiv : the Preprint Server For... Jun 2024During development, microglia prune excess synapses to refine neuronal circuits. In neurodegeneration, the role of microglia-mediated synaptic pruning in circuit...
UNLABELLED
During development, microglia prune excess synapses to refine neuronal circuits. In neurodegeneration, the role of microglia-mediated synaptic pruning in circuit remodeling and dysfunction is important for developing therapies aimed at modulating microglial function. Here we analyzed the role of microglia in the synapse disassembly of degenerating postsynaptic neurons in the inner retina. After inducing transient intraocular pressure elevation to injure retinal ganglion cells, microglia increase in number, shift to ameboid morphology, and exhibit greater process movement. Furthermore, due to the greater number of microglia, there is increased colocalization of microglia with synaptic components throughout the inner plexiform layer and with excitatory synaptic sites along individual ganglion cell dendrites. Microglia depletion partially restores ganglion cell function, suggesting that microglia activation may be neurotoxic in early neurodegeneration. Our results demonstrate the important role of microglia in synapse disassembly in degenerating circuits, highlighting their recruitment to synaptic sites early after neuronal injury.
HIGHLIGHTS
Early after transient intraocular pressure elevation: Microglia increase in number, complexity, and process movementMicroglia-synaptic contacts increase in the inner plexiform layerMicroglia-synaptic contacts increase on retinal ganglion cell dendritesMicroglia depletion partially restores ganglion cell function.
PubMed: 38915631
DOI: 10.1101/2024.06.13.598914 -
Cureus May 2024Migraine is characterized by recurrent episodes of unilateral, pulsating headaches. At the cerebral and ocular levels, it is recognized that the vascular narrowing and...
BACKGROUND
Migraine is characterized by recurrent episodes of unilateral, pulsating headaches. At the cerebral and ocular levels, it is recognized that the vascular narrowing and loss of blood flow are transient; however, the chronic nature of migraine may result in long-term functional and structural changes in these structures. It could result in axonal loss and an alteration in the thickness of the retinal nerve fiber layers (RNFL). This study aimed to measure the RNFL thickness, which provides a useful indication of the state of the axons and the loss of ganglion cells in migraine patients, and to find out if RNFL thickness and the clinical features of migraine are correlated.
MATERIALS AND METHODS
Sixty patients with migraine and 60 age-gender-matched controls were recruited. A complete neurological and ophthalmological examination was performed, and spectral-domain optical coherence tomography (SD-OCT) was done to measure RNFL.
RESULTS
All quadrants of the retina on both sides showed non-statistically significant differences in RNFL thickness between migraine patients and controls (p-value >0.05). Furthermore, in all retinal quadrants on both sides, there was no statistically significant difference in RNFL thickness between migraine patients with aura and those without aura (p-value >0.05). Significant correlations were found between the duration of migraine disease and the superior RNFL thickness of both eyes, as well as the inferior RNFL in the right eye. There was also a significant correlation between the headache attack duration and RNFL thickness of the superior retina (p<0.05), Conclusion: Our key finding was that when comparing migraine patients to controls, RNFL thickness did not significantly change; however, the duration of migraine disease did significantly affect RNFL thickness.
PubMed: 38910687
DOI: 10.7759/cureus.60909 -
American Journal of Ophthalmology Jun 2024Exfoliation syndrome (XFS) is a systemic connective tissue disorder with elusive pathophysiology. We hypothesize that a mouse model with elastic fiber defects caused by...
PURPOSE
Exfoliation syndrome (XFS) is a systemic connective tissue disorder with elusive pathophysiology. We hypothesize that a mouse model with elastic fiber defects caused by lack of lysyl oxidase like 1 (LOXL1 encoded by Loxl1), combined with microfibril deficiency due to Fbn1 mutation (encoding fibrillin-1, Fbn1) will display ocular and systemic phenotypes of XFS.
METHODS
Loxl1 was crossed with Fbn1 to create double mutant (dbm) mice. Intraocular pressure (IOP), visual acuity (VA), electroretinogram (ERG) and biometry were characterized in 4 genotypes (wt, Fbn1, Loxl1, dbm) at 16 weeks old. Optic nerve area was measured by ImageJ and axon counting was achieved by AxonJ. Deep whole-body phenotyping was performed in wt and dbm mice. Two-tailed Student's t-test was used for statistical analysis.
RESULTS
There was no difference in IOP between the 4 genotypes. VA was significantly reduced only in dbm mice. The majority of biometric parameters showed significant differences in all 3 mutant genotypes compared to wt, and dbm had exacerbated anomalies compared to single mutants. Dbm mice showed reduced retinal function and significantly enlarged ON area when compared with wt. Dbm mice exhibited severe systemic phenotypes related to abnormal elastic fibers, such as pelvic organ prolapse, cardiovascular and pulmonary abnormalities.
CONCLUSIONS
Ocular and systemic findings in dbm mice support functional overlap between fibrillin-1 and LOXL1, two prominent components of exfoliation material. Although no elevated IOP or reduction of axon numbers was detected in dbm mice at 16-week-old, their reduced retinal function and enlarged ON area indicate early retinal ganglion cell dysfunction. Dbm mice also provide insight on the link between XFS and systemic diseases in humans.
PubMed: 38909741
DOI: 10.1016/j.ajo.2024.06.015 -
Cell Communication and Signaling : CCS Jun 2024Mitochondria are central to endothelial cell activation and angiogenesis, with the RNA polymerase mitochondrial (POLRMT) serving as a key protein in regulating...
Mitochondria are central to endothelial cell activation and angiogenesis, with the RNA polymerase mitochondrial (POLRMT) serving as a key protein in regulating mitochondrial transcription and oxidative phosphorylation. In our study, we examined the impact of POLRMT on angiogenesis and found that its silencing or knockout (KO) in human umbilical vein endothelial cells (HUVECs) and other endothelial cells resulted in robust anti-angiogenic effects, impeding cell proliferation, migration, and capillary tube formation. Depletion of POLRMT led to impaired mitochondrial function, characterized by mitochondrial depolarization, oxidative stress, lipid oxidation, DNA damage, and reduced ATP production, along with significant apoptosis activation. Conversely, overexpressing POLRMT promoted angiogenic activity in the endothelial cells. In vivo experiments demonstrated that endothelial knockdown of POLRMT, by intravitreous injection of endothelial specific POLRMT shRNA adeno-associated virus, inhibited retinal angiogenesis. In addition, inhibiting POLRMT with a first-in-class inhibitor IMT1 exerted significant anti-angiogenic impact in vitro and in vivo. Significantly elevated expression of POLRMT was observed in the retinal tissues of streptozotocin-induced diabetic retinopathy (DR) mice. POLRMT endothelial knockdown inhibited pathological retinal angiogenesis and mitigated retinal ganglion cell (RGC) degeneration in DR mice. At last, POLRMT expression exhibited a substantial increase in the retinal proliferative membrane tissues of human DR patients. These findings collectively establish the indispensable role of POLRMT in angiogenesis, both in vitro and in vivo.
Topics: Humans; Animals; Human Umbilical Vein Endothelial Cells; Mice; Mitochondria; DNA-Directed RNA Polymerases; Diabetic Retinopathy; Mice, Inbred C57BL; Cell Proliferation; Neovascularization, Pathologic; Male; Neovascularization, Physiologic; Cell Movement; Apoptosis; Angiogenesis
PubMed: 38907279
DOI: 10.1186/s12964-024-01712-9 -
Experimental Eye Research Jun 2024The optic nerve head (ONH) is a complex structure wherein the axons of the retinal ganglion cells extrude from the eyeball through three openings: 1) the Bruch's... (Review)
Review
The optic nerve head (ONH) is a complex structure wherein the axons of the retinal ganglion cells extrude from the eyeball through three openings: 1) the Bruch's membrane opening (BMO) in the retinal layer, 2) the anterior scleral canal opening in the anterior scleral layer, and 3) the lamina cribrosa (LC). Eyeball expansion during growth induces an offset among openings, since the expansion affects the inner retinal and outer scleral layers differently: the posterior polar retinal structure is preserved by the preferential growth in the equatorial region, whereas no such regional difference is observed in the scleral layer. The various modes and extents of eyeball expansion result in diverse directionality and amount of offset among openings, which causes diverse ONH morphology in adults, especially in myopia. In this review, we summarize the ONH changes that occur during myopic axial elongation. These changes were observed prospectively in our previous studies, wherein LC shift and subsequent offset from the BMO center could be predicted by tracing the central retinal vascular trunk position. This offset induces the formation of γ-zone parapapillary atrophy or externally oblique border tissue. As a presumptive site of glaucomatous damage, the LC/BMO offset may render the LC pores in the opposite direction more vulnerable. To support such speculation, we also summarize the relationship between LC/BMO offset and glaucomatous damage. Indeed, LC/BMO offset is not only the cause of diverse ONH morphology in adults, but is also, potentially, an important clinical marker for assessment of glaucoma.
PubMed: 38906240
DOI: 10.1016/j.exer.2024.109975 -
International Journal of Medical... 2024Synuclein family members (Snca, Sncb, and Scng) are expressed in the retina, but their precise locations and roles are poorly understood. We performed an extensive...
Synuclein family members (Snca, Sncb, and Scng) are expressed in the retina, but their precise locations and roles are poorly understood. We performed an extensive analysis of the single-cell transcriptome in healthy and injured retinas to investigate their expression patterns and roles. We observed the expression of all synuclein family members in retinal ganglion cells (RGCs), which remained consistent across species (human, mouse, and chicken). We unveiled differential expression of Snca across distinct clusters (highly expressed in most), while Sncb and Sncg displayed uniform expression across all clusters. Further, we observed a decreased expression in RGCs following traumatic axonal injury. However, the proportion of α-Syn-positive RGCs in all RGCs and α-Syn-positive intrinsically photosensitive retinal ganglion cells (ipRGCs) in all ipRGCs remained unaltered. Lastly, we identified changes in communication patterns preceding cell death, with particular significance in the pleiotrophin-nucleolin (Ptn-Ncl) and neural cell adhesion molecule signaling pathways, where communication differences were pronounced between cells with varying expression levels of Snca. Our study employs an innovative approach using scRNA-seq to characterize synuclein expression in health retinal cells, specifically focusing on RGC subtypes, advances our knowledge of retinal physiology and pathology.
Topics: Animals; Retinal Ganglion Cells; Humans; Mice; alpha-Synuclein; gamma-Synuclein; beta-Synuclein; Chickens; Transcriptome; Single-Cell Analysis; Retina; Neoplasm Proteins
PubMed: 38903914
DOI: 10.7150/ijms.95598 -
Frontiers in Cellular Neuroscience 2024Mechanical sensitive channels expressed in mammalian retinas are effectors of elevated pressure stresses, but it is unclear how their activation affects visual function...
INTRODUCTION
Mechanical sensitive channels expressed in mammalian retinas are effectors of elevated pressure stresses, but it is unclear how their activation affects visual function in pressure-related retinal disorders.
METHODS
This study investigated the role of the transient potential channel vanilloid TRPV4 in photoreceptors and rod bipolar cells (RBCs) with immunohistochemistry, confocal microscopy, electroretinography (ERG), and patch-clamp techniques.
RESULTS
TRPV4 immunoreactivity (IR) was found in the outer segments of photoreceptors, dendrites and somas of PKCα-positive RBCs and other BCs, plexiform layers, and retinal ganglion cells (RGCs) in wild-type mice. TRPV4-IR was largely diminished in the retinas of homozygous TRPV4 transgenic mice. Genetically suppressing TRPV4 expression moderately but significantly enhanced the amplitude of ERG a- and b-waves evoked by scotopic and mesopic lights (0.55 to 200 Rh*rod s) and photopic lights (10-10 Rh*rod s) compared to wild-type mice in fully dark-adapted conditions. The implicit time evoked by dim lights (0.55 to 200 Rh*rod s) was significantly decreased for b-waves and elongated for a-waves in the transgenic mice. ERG b-wave evoked by dim lights is primarily mediated by RBCs, and under voltage-clamp conditions, the latency of the light-evoked cation current in RBCs of the transgenic mice was significantly shorter compared to wild-type mice. About 10% of the transgenic mice had one eye undeveloped, and the percentage was significantly higher than in wild-type mice.
CONCLUSIONS
The data indicates that TRPV4 involves ocular development and is expressed and active in outer retinal neurons, and interventions of TRPV4 can variably affect visual signals in rods, cones, RBCs, and cone ON BCs.
PubMed: 38903773
DOI: 10.3389/fncel.2024.1404929 -
American Journal of Ophthalmology Jun 2024To evaluate ophthalmological, neurological, radiological, and laboratory data in patients with multiple sclerosis (MS) and to identify new ophthalmological factors that...
PURPOSE
To evaluate ophthalmological, neurological, radiological, and laboratory data in patients with multiple sclerosis (MS) and to identify new ophthalmological factors that could be helpful as biomarkers of the disease, potentially leading to an earlier prediction of disease course and disability progression.
DESIGN
Retrospective, cross-sectional-study.
METHODS
Best-corrected visual acuity (BCVA), ophthalmological biomicroscopy of the anterior segment and fundus, structural optical coherence tomography (OCT) with retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC), and OCT Angiography (OCTA) with vascular density (VD) were performed. The following clinical and neuro-radiological features were assessed: MS phenotype, disease duration, clinical severity, type of treatment, and T2-weighted lesion load plus T1-weighted Gd+-enhancing lesion number on the last brain and spinal cord MRI.
RESULTS
One hundred and six patients (212 eyes) were analyzed. Sixty-six of them (62.2 %) had MS and 40 (37.8%) were matched healthy controls (HCs). patients with MS showed lower RNFL, GCC, and VD in the radial peripapillary capillary plexus than controls in both eyes (p<0.05). By Performing a logistic regression with a distinct MS outcome for both eyes, we were able to demonstrate that the value that was most predictive of MS was the average GCC thickness (p=0.009). Regression analysis demonstrated that patients with a higher T2-weighted lesions showed a lower RNFL thickness value and reduced GCC and VD values than those with a low lesion load (p<0.01 and p<0.05, respectively). Similarly, relapsing MS patients showed lower RNFL values (p<0.05).
CONCLUSIONS
Several OCT- and OCTA-optic nerve parameters could be useful prognostic biomarkers for the MS disease course in clinical practice. However, it is necessary to do additional research with larger sample sizes in order to validate these findings.
PubMed: 38901720
DOI: 10.1016/j.ajo.2024.06.011 -
Nature Communications Jun 2024Retinal optical coherence tomography has been identified as biomarker for disease progression in relapsing-remitting multiple sclerosis (RRMS), while the dynamics of...
Retinal optical coherence tomography has been identified as biomarker for disease progression in relapsing-remitting multiple sclerosis (RRMS), while the dynamics of retinal atrophy in progressive MS are less clear. We investigated retinal layer thickness changes in RRMS, primary and secondary progressive MS (PPMS, SPMS), and their prognostic value for disease activity. Here, we analyzed 2651 OCT measurements of 195 RRMS, 87 SPMS, 125 PPMS patients, and 98 controls from five German MS centers after quality control. Peripapillary and macular retinal nerve fiber layer (pRNFL, mRNFL) thickness predicted future relapses in all MS and RRMS patients while mRNFL and ganglion cell-inner plexiform layer (GCIPL) thickness predicted future MRI activity in RRMS (mRNFL, GCIPL) and PPMS (GCIPL). mRNFL thickness predicted future disability progression in PPMS. However, thickness change rates were subject to considerable amounts of measurement variability. In conclusion, retinal degeneration, most pronounced of pRNFL and GCIPL, occurs in all subtypes. Using the current state of technology, longitudinal assessments of retinal thickness may not be suitable on a single patient level.
Topics: Humans; Retinal Degeneration; Male; Female; Tomography, Optical Coherence; Adult; Middle Aged; Disease Progression; Multiple Sclerosis, Relapsing-Remitting; Retina; Multiple Sclerosis, Chronic Progressive; Magnetic Resonance Imaging; Prognosis; Nerve Fibers; Retinal Ganglion Cells
PubMed: 38897994
DOI: 10.1038/s41467-024-49309-7 -
Cells May 2024BAX plays an essential role in retinal ganglion cell (RGC) death induced by optic nerve injury. Recently, we developed M109S, an orally bioactive and cytoprotective...
BAX plays an essential role in retinal ganglion cell (RGC) death induced by optic nerve injury. Recently, we developed M109S, an orally bioactive and cytoprotective small compound (CPSC) that inhibits BAX-mediated cell death. We examined whether M109S can protect RGC from optic nerve crush (ONC)-induced apoptosis. M109S was administered starting 5 h after ONC for 7 days. M109S was orally administered in two groups (5 mg/kg twice a day or 7.5 mg/kg once a day). The retina was stained with anti-BRN3A and cleaved Caspase-3 (active Caspase-3) that are the markers of RGC and apoptotic cells, respectively. ONC decreased the number of BRN3A-positive RGC and increased the number of active Caspase-3-expressing apoptotic cells. In ONC-treated retina, there were cells that were double stained with anti-BRN3A and ant-cleaved Caspase-3, indicating that apoptosis in BRN3A-positive RGCs occurred. M109S inhibited the decrease of BRN3A-positive cells whereas it inhibited the increase of active Caspase-3-positive cells in the retina of ONC-treated mice, suggesting that M109S inhibited apoptosis in RGCs. M109S did not induce detectable histological damage to the lungs or kidneys in mice, suggesting that M109S did not show toxicities in the lung or kidneys when the therapeutic dose was used. The present study suggests that M109S is effective in rescuing damaged RGCs. Since M109S is an orally bioactive small compound, M109S may become the basis for a portable patient-friendly medicine that can be used to prevent blindness by rescuing damaged optic nerve cells from death.
Topics: Animals; Retinal Ganglion Cells; Mice; Optic Nerve Injuries; Apoptosis; Nerve Crush; Male; Caspase 3; Mice, Inbred C57BL; Cytoprotection; Optic Nerve
PubMed: 38891043
DOI: 10.3390/cells13110911