Disassembly and rewiring of a mature converging excitatory circuit following injury

Santina, Luca Della; Yu, Alfred K.; Harris, Scott; Soliño, Manuel; Ruiz, Tonatiuh Garcia; Most, Jesse; Kuo, Yien–Ming; Dunn, Felice A.; Ou, Yvonne

doi:10.1016/j.celrep.2021.109463

Cited by 14 publications

(19 citation statements)

References 30 publications

(55 reference statements)

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“…In addition, other authors have characterized the presence of calbindin expressed in ONs-αRGCs (in addition to the labeling of a subpopulation of amacrine cells; Krieger et al, 2017 ; Sonoda et al, 2020 ) which, when colocalized with an αRGC pan-marker, allows for reliable detection of ONs-αRGCs. Previous studies have documented that these M4-ipRGCs (ONs-αRGCs) are more resistant to retinal injury (El-Danaf and Huberman, 2015 ; Ou et al, 2016 ; Tran et al, 2019 ), due to their ability to alter their synaptic connectivity pattern after injury to promote survival (Della Santina et al, 2021 ). However, there is not a complete consensus on this characteristic, as in other studies, M4-ipRGCs have not been more resistant than the rest of the RGCs (Gallego-Ortega et al, 2021 ; Gao et al, 2022 ), reviewed in Tran et al ( 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Alpha retinal ganglion cells in pigmented mice retina: number and distribution

et al. 2022

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Purpose: To identify and characterize numerically and topographically the population of alpha retinal ganglion cells (αRGCs) and their subtypes, the sustained-response ON-center αRGCs (ONs-αRGCs), which correspond to the type 4 intrinsically photosensitive RGCs (M4-ipRGCs), the transient-response ON-center αRGCs (ONt-αRGCs), the sustained-response OFF-center αRGCs (OFFs-αRGCs), and the transient-response OFF-center αRGCs (OFFt-αRGCs) in the adult pigmented mouse retina.Methods: The αRGC population and its subtypes were studied in flat-mounted retinas and radial sections immunodetected against non-phosphorylated high molecular weight neurofilament subunit (SMI-32) or osteopontin (OPN), two αRGCs pan-markers; Calbindin, expressed in ONs-αRGCs, and amacrines; T-box transcription factor T-brain 2 (Tbr2), a key transcriptional regulator for ipRGC development and maintenance, expressed in ipRGCs and GABA-displaced amacrine cells; OPN4, an anti-melanopsin antibody; or Brn3a and Brn3c, markers of RGCs. The total population of RGCs was counted automatically and αRGCs and its subtypes were counted manually, and color-coded neighborhood maps were used for their topographical representation.Results: The total mean number of αRGCs per retina is 2,252 ± 306 SMI32+αRGCs and 2,315 ± 175 OPN+αRGCs (n = 10), representing 5.08% and 5.22% of the total number of RGCs traced from the optic nerve, respectively. αRGCs are distributed throughout the retina, showing a higher density in the temporal hemiretina. ONs-αRGCs represent ≈36% [841 ± 110 cells (n = 10)] of all αRGCs and are located throughout the retina, with the highest density in the temporal region. ONt-αRGCs represent ≈34% [797 ± 146 cells (n = 10)] of all αRGCs and are mainly located in the central retinal region. OFF-αRGCs represent the remaining 32% of total αRGCs and are divided equally between OFFs-αRGCs and OFFt-αRGCs [363 ± 50 cells (n = 10) and 376 ± 36 cells (n = 10), respectively]. OFFs-αRGCs are mainly located in the supero-temporal peripheral region of the retina and OFFt-αRGCs in the mid-peripheral region of the retina, especially in the infero-temporal region.Conclusions: The combination of specific antibodies is a useful tool to identify and study αRGCs and their subtypes. αRGCs are distributed throughout the retina presenting higher density in the temporal area. The sustained ON and OFF response subtypes are mainly located in the periphery while the transient ON and OFF response subtypes are found in the central regions of the retina.

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Section: Introductionmentioning

confidence: 99%

Alpha retinal ganglion cells in pigmented mice retina: number and distribution

et al. 2022

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“…The increase in synaptic plasticity is conducive to optimizing the neural network and the maturity of brain function. It is crucial for stem cell-based therapies to restore functional recovery [38]. Our study shows that NSCs intranasal delivery plays a positive role in promoting the regulation of plasticity and stability, and the reduction in BNE may be an important indicator of the function improvement of the cerebral network in patients with CP.…”

Section: Discussionmentioning

confidence: 66%

Safety and efficacy outcomes after intranasal administration of neural stem cells in cerebral palsy: a randomized phase 1/2 controlled trial

Liu

Wang

et al. 2023

Stem Cell Res Ther

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Background Neural stem cells (NSCs) are believed to have the most therapeutic potential for neurological disorders because they can differentiate into various neurons and glial cells. This research evaluated the safety and efficacy of intranasal administration of NSCs in children with cerebral palsy (CP). The functional brain network (FBN) analysis based on electroencephalogram (EEG) and voxel-based morphometry (VBM) analysis based on T1-weighted images were performed to evaluate functional and structural changes in the brain. Methods A total of 25 CP patients aged 3–12 years were randomly assigned to the treatment group (n = 15), which received an intranasal infusion of NSCs loaded with nasal patches and rehabilitation therapy, or the control group (n = 10) received rehabilitation therapy only. The primary endpoints were the safety (assessed by the incidence of adverse events (AEs), laboratory and imaging examinations) and the changes in the Gross Motor Function Measure-88 (GMFM-88), the Activities of Daily Living (ADL) scale, the Sleep Disturbance Scale for Children (SDSC), and some adapted scales. The secondary endpoints were the FBN and VBM analysis. Results There were only four AEs happened during the 24-month follow-up period. There was no significant difference in the laboratory examinations before and after treatment, and the magnetic resonance imaging showed no abnormal nasal and intracranial masses. Compared to the control group, patients in the treatment group showed apparent improvements in GMFM-88 and ADL 24 months after treatment. Compared with the baseline, the scale scores of the Fine Motor Function, Sociability, Life Adaptability, Expressive Ability, GMFM-88, and ADL increased significantly in the treatment group 24 months after treatment, while the SDSC score decreased considerably. Compared with baseline, the FBN analysis showed a substantial decrease in brain network energy, and the VBM analysis showed a significant increase in gray matter volume in the treatment group after NSCs treatment. Conclusions Our results showed that intranasal administration of NSCs was well-tolerated and potentially beneficial in children with CP. Trial registration: The study was registered in ClinicalTrials.gov (NCT03005249, registered 29 December 2016, https://www.clinicaltrials.gov/ct2/show/NCT03005249) and the Medical Research Registration Information System (CMR-20161129-1003).

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“…Next, we studied the integrity of ON vs. OFF bipolar cell axons following glaucoma-like injury. Immunostaining against Sty2, which labels the axon terminals of type 2 and 6 bipolar cells ( 20 ), has verified the preservation of type 6 ON bipolar cell axons but OFF axons remain obscure ( 62 ). We distinguished the ON and OFF bipolar cells by the IPL depth of axon terminals, quantifying the entire population in the same wholemounts.…”

Section: Resultsmentioning

confidence: 98%

Axonal architecture of the mouse inner retina revealed by second harmonic generation

et al. 2022

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We describe a novel method for visualizing the network of axons in the unlabeled fresh wholemount retina. The intrinsic radiation of second harmonic generation (SHG) was utilized to visualize single axons of all major retinal neurons, i.e. photoreceptors, horizontal cells, bipolar cells, amacrine cells, and the retinal ganglion cells. The cell types of SHG + axons were determined using transgenic GFP/YFP mice. New findings were obtained with retinal SHG imaging: Müller cells do not maintain uniformly polarized microtubules in the processes; SHG + axons of bipolar cells terminate in the inner plexiform layer (IPL) in a subtype-specific manner; a subset of amacrine cells, presumably the axon-bearing types, emits SHG; and the axon-like neurites of amacrine cells provide a cytoskeletal scaffolding for the IPL stratification. To demonstrate the utility, retinal SHG imaging was applied for testing whether the inner retina is preserved in glaucoma, using DBA/2 mice as a model of glaucoma and DBA/2-Gpnmb + as the non-glaucomatous control. It was found that the morphology of the inner retina was largely intact in glaucoma and the pre-synaptic compartments to the retinal ganglion cells were uncompromised. It proves retinal SHG imaging as a promising technology for studying the physiological and diseased retinas in 3D.

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Disassembly and rewiring of a mature converging excitatory circuit following injury

Cited by 14 publications

References 30 publications

Alpha retinal ganglion cells in pigmented mice retina: number and distribution

Alpha retinal ganglion cells in pigmented mice retina: number and distribution

Safety and efficacy outcomes after intranasal administration of neural stem cells in cerebral palsy: a randomized phase 1/2 controlled trial

Axonal architecture of the mouse inner retina revealed by second harmonic generation

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