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Photoreceptor degeneration, structural remodeling and glial activation: a morphological study on a genetic mouse model for pericyte deficiency
Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
2014 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 279, p. 269-284Article in journal (Refereed) Published
Abstract [en]

Interaction between pericytes and endothelial cells via platelet-derived growth factor B (PDGF-B) signaling is critical for the development of the retinal microvasculature. The PDGF-B retention motif controls the spatial distribution range of the growth factor in the vicinity of its producing endothelial cells allowing its recognition by PDGF receptor beta-(PDGFR-beta)-carrying pericytes; this promotes recruitment of pericytes to the vascular basement membrane. Impairment of the PDGF-B signaling mechanism causes development of vascular abnormalities, and in the retina this consequently leads to defects in the neurological circuitry. The vascular pathology in the pdgf-b(ret/ret) (PDGF-B retention motif knockout) mouse retina has been previously reported; our study investigates the progressive neuronal defects and changes in the retinal morphology of this pericyte-deficient mouse model. Immunohistochemical analysis revealed retinal injuries to occur as early as postnatal day (P) 10 with substantial damage progressing from P15 and onward. Vascular abnormalities were apparent from P10, however, prominent neuronal defects were mostly observed from P15, beginning with the compromised integrity of the laminated retinal structure characterized by the presence of rosettes and focally distorted regions. Photoreceptor degeneration was observed by loss of both rod and cone cells, including the disassembly and altered structure of their synaptic terminals. Significant shortening of cone outer segments was observed from P10 and later stages; however, decrease in cone density was only observed at P28. Disorganization and dendrite remodeling of rod bipolar cells also added to the diminished neural and synaptic integrity. Moreover, in response to retinal injuries, Muller and microglial cells were observed to be in the reactive phenotype from P15 and onward. Such a sequence of events indicates that the pdgf-b(ret/ret) mouse model displays a short time frame between P10 and P15, during which the retina shifts to a retinopathic phase by the development of prominently altered morphological features.

Place, publisher, year, edition, pages
2014. Vol. 279, p. 269-284
Keywords [en]
photoreceptor degeneration, cell death, rosette, synapse, microglia, Müller cells
National Category
Neurosciences
Research subject
Neurology
Identifiers
URN: urn:nbn:se:oru:diva-38893DOI: 10.1016/j.neuroscience.2014.09.013ISI: 000343633800022PubMedID: 25224828Scopus ID: 2-s2.0-84907487118OAI: oai:DiVA.org:oru-38893DiVA, id: diva2:765629
Note

Funding Agencies:

Faculty of Medicine at Örebro University

Signhild Engkvist Foundation

Ögonfonden

Crown Princess Margaretas Committee for the Blind

Gun and Bertil Stohnes Foundation

Karolinska Fonder och Stiftelser

Available from: 2014-11-24 Created: 2014-11-21 Last updated: 2018-01-11Bibliographically approved
In thesis
1. Photoreceptor degeneration, second order neuron remodeling and glia reactivity in an in vivo and in vitro model of retinal neurodegeneration
Open this publication in new window or tab >>Photoreceptor degeneration, second order neuron remodeling and glia reactivity in an in vivo and in vitro model of retinal neurodegeneration
2016 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Photoreceptors have the ability to last during the entire lifespan of an individual. Being the first line of neurons in the visual transduction pathway, their health and maintenance is eminent for proper retinal function. However, photoreceptors are susceptible to neurodegenerative retinal dystrophies. A number of retinal pathologies such as retinitis pigmentosa, age-related amacular degeneration and diabetic retinopathy have been linked to photoreceptor death. Moreover, photoreceptor degeneration has been shown to affect downstream inner nuclear layer cells as well as induce reactive responses from Müller cells and microglia. Since current treatments are ineffective in preventing the degeneration of these neurons, intense research is still underway to discover novel treatment modalities. In this thesis, photoreceptor degeneration was assessed in an in vivo and in vitro model of neurodegeneration. Moreover, a possible mode of preserving these neurons by the use of human neural progenitor cells (hNPCs) was investigated. The in vivo pdgf-bret/ret (platelet derived growth factor-b retention motif knockout) mouse model, which shows severe vascular pathology as a result of detachment of pericytes from the vascular endothelium, was studied during the first postnatal month. In a short time span, i.e. between postnatal day (P)10 and P15, retinopathic features were observed. Photoreceptor degeneration related to cell death, cone outer segment (OS) shortening and synapse disassembly in the outer plexiform layer (OPL) was seen. The second order rod bipolar cells underwent remodeling and the Müller cells became gliotic with increased expression of GFAP (glial fibrillary acidic protein). Microglial cells were also observed to convert to their reactive amoeboid-like phenotype. These features seemed to become more severe in the older P28 mutants. In the in vitro porcine retinal explant model, photoreceptor death significantly increased by 3 days in vitro (div). This was associated with loss of cone OSs, opsin mislocalization and loss of synaptic integrity in the OPL. Horizontal cell death and remodeling was also observed together with a severe gliotic response from the Müller cells. Human neural progenitor cell cocultured explants for 3 div had the ability to preserve photoreceptor survival by means of OS conservation, better opsin trafficking and maintaining synaptic integrity. However, Müller cell gliosis was only mitigated by a decreased density of GFAP immunoreactive Müller cells. In conclusion, both the in vivo and in vitro model of neurodegeneration demonstrate the vulnerability of photoreceptors to various mechanisms of retinal injury. Interestingly, hNPC derived neurotrophic factors had neuroprotective qualities in 3 div porcine retinal explants.

Place, publisher, year, edition, pages
Örebro: Örebro University, 2016. p. 40
National Category
Other Basic Medicine
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-53596 (URN)
Presentation
2016-11-23, Örebro universitet, Campus USÖ, Hörsal C1, Södra Grev Rosengatan 30, Örebro, 13:15 (Swedish)
Available from: 2016-11-21 Created: 2016-11-21 Last updated: 2018-01-13Bibliographically approved

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Mollick, TanzinaJohansson, Kjell

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