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Histone Deacetylases Contribute to Excitotoxicity-Triggered Degeneration of Retinal Ganglion Cells In Vivo

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Abstract

Excitotoxicity is known to modulate the nuclear accumulation, and thus activity state, of histone deacetylases (HDACs) in pyramidal neurons. In the retina, deregulation in activity and expression of different HDACs has been linked to pathological conditions such as retinitis pigmentosa, retinal ischemia, glaucoma, and acute optic nerve injury. Up to now, however, the effects of in vivo excitotoxicity on the different HDACs in retinal ganglion cells (RGCs) have not been thoroughly investigated. Here, we injected adult mice intravitreally with N-methyl-D-aspartate (NMDA) as a mean to trigger excitotoxicity-mediated RGC degeneration and we detected time-dependent loss of RGCs at 1 and 7 days after the insult. Further, we characterized the subcellular localization of HDACs belonging to class I (HDAC1, HDAC3), IIa (HDAC4, HDAC5, HDAC7, HDAC9), IIb (HDAC6, HDAC10), and IV (HDAC11) in RGCs. Our analyses revealed a differential pattern of HDACs nuclear distribution in RGCs following excitotoxicity. After 1 day, HDAC3, HDAC5, HDAC6, HDAC7, and HDAC11 showed altered subcellular localization in RGCs while 7 days after the excitotoxic insult, HDAC4 and HDAC9 were the only HDACs displaying changes in their subcellular distribution. Moreover, we found that in vivo selective inhibition of HDAC1/3 or HDAC4/5 via MS-275 (entinostat) or LMK-235, respectively, could prevent ongoing RGC degeneration. In conclusion, our results point towards a role of HDACs in RGC degeneration and identify HDAC1/3 and HDAC4/5 as potential therapeutic targets to treat degenerative retinal diseases.

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Acknowledgments

The authors thank Dr. Bettina Buchthal for her help with the establishment of intravitreal injections. DM is a member of the Excellence Cluster CellNetworks at Heidelberg University. Part of the pictures was acquired at the Nikon Imaging Center at Heidelberg University.

Funding

This work was supported by the FOR2325 grant (project 2) and SFB1158 (project A08) of the Deutsche Forschungsgemeinschaft (DFG) to DM, the FRONTIER grant of Heidelberg University to DM, Italian PRIN 2016 (prot. 20152TE5PK to AM), AIRC 2016 (n. 19162 to AM), and PE-2013-02355271 to AM.

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  1. Neurobiology, Interdisciplinary Center for Neurosciences, Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany

    Annabelle Schlüter, Bahar Aksan & Daniela Mauceri

  2. Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy

    Rossella Fioravanti, Sergio Valente & Antonello Mai

  3. Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy

    Antonello Mai

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Correspondence to Daniela Mauceri.

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This article does not contain any studies with human participants performed by any of the authors. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. All procedures were approved by the local governing body for animal welfare (Regierungspräsidium Karlsruhe).

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The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. DM is one of the founders and shareholders of FundaMental Pharma GmbH.

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Schlüter, A., Aksan, B., Fioravanti, R. et al. Histone Deacetylases Contribute to Excitotoxicity-Triggered Degeneration of Retinal Ganglion Cells In Vivo. Mol Neurobiol 56, 8018–8034 (2019). https://doi.org/10.1007/s12035-019-01658-x

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