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SHARON JIYOON JUNG, Ji-Heon Choi, Seung Hee Lee, Sun Sook Paik, Hong Lim Kim, Jin Woo Kim, IN-BEOM KIM; Structural and Functional Alterations in Tuberous Sclerosis Complex 1 (Tsc1)-Deficient Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2019;60(9):582. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The mammalian target of rapamycin complex 1 (mTORC1) that interacts with a serine/threonine protein kinase mTOR regulates cell proliferation and growth. A recent study (Choi et al., 2018) has shown that mTORC1 accelerates mouse retinal development. In this study, we examined structural and functional changes in mature retinas tuberous sclerosis complex 1 (Tsc1)-deficient (Tsc1flox/flox;Chx10-Cre, Tsc1-cko) mice in which mTORC1 is hyperactive.
Tsc1-cko mice were generated from Tsc1flox/flox (Jackson Laboratory, Maine, USA) and Chx10-Cre (a gift from Dr. Connie Cepko, Harvard University). Animals were selected from 3 groups of Tsc1-cko (1, 3, and 6 months old) and age-matched control mice. To assess retinal structural changes, double-label immunofluorescence and electron microscopy (EM) were performed. PAS (periodic acid-Schiff) staining was conducted to examine specific histopathological findings. To evaluate retinal function, full-field electroretinography (ERG) was performed under scotopic and photopic conditions.
In histology, Tsc1-cko mouse retina was characterized by thick inner nuclear layer with large-sized bipolar cell somata and thin outer nuclear layer (ONL), compared to control mouse retina. The arrangement of protein kinase C-IR rod bipolar cells (RBCs) was prominently disrupted. Over time, dendrites of RBCs penetrating into the ONL and abnormal tufts were observed. Their axon terminals were ramified and terminated within sublamina b of the IPL. Electron microscopy revealed ectopic ribbon synapses and atypical round shaped synaptic ribbons in the ONL. Interestingly, electron dense granules, which showed positive for PAS staining were seen throughout the retinal neurons in Tsc1-cko mouse. In ERG recordings, scotopic and photopic b-waves were significantly increased in Tsc1-cko mouse (p<0.05), compared to control group. The peak amplitudes of a- and b-waves were observed at 2 months old mice, and gradually decreased thereafter.
In Tsc1-cko mouse retina, morphological changes mainly occur in the outer retinal neurons, such as photoreceptors and bipolar cells, at both cellular and synaptic levels. These structural and functional changes in Tsc1-cko mouse retina demonstrate that mTORC1 hyperactivation causes robust alterations in retinal structure and function as well as developmental acceleration, revealing importance of mTORC1 in retinal development.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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