Targeting HDAC3 in the DBA/2J spontaneous mouse model of glaucoma
Introduction
Glaucoma is the second-leading cause of blindness in the world and is associated with degeneration of the optic nerve and loss of retinal ganglion cells (RGCs) (Tham et al., 2014). To date, no therapeutic treatment has emerged to directly prevent RGC loss and preserve vision. High intraocular pressure (IOP), or ocular hypertension, is the most common risk factor associated with glaucomatous pathology at the optic nerve head (Quigley et al., 1994), and animal models to investigate the pathological effects of ocular hypertension include those in mice, rats, cats, dogs and primates (Khan et al., 2015; Kuchtey et al., 2011; Kuehn et al., 2016; Morrison et al., 2005; Morrison et al., 1998; Pederson and Gaasterland, 1984; Radius and Pederson, 1984; Sappington et al., 2010). Previously, it was shown in mouse models that retinal ganglion cells die via intrinsic apoptosis following acute or chronic optic nerve insult, and when pro-apoptotic factor BAX is knocked out, RGCs do not die (Li et al., 2000; Libby et al., 2005b; Semaan et al., 2010). In surviving Bax-deficient RGCs, gene silencing and nuclear atrophic events such as histone deacetylation, chromatin condensation, and deterioration of the nuclear membrane still occur, indicating that these events happen prior to committed cell death (Janssen et al., 2013).
Histone deacetylation is known to play an important role in the early events of nuclear atrophy in RGCs, and after optic nerve crush (ONC), histone deacetylation peaks at 5 days after injury (Pelzel et al., 2010). Recent studies have shown that histone deacetylases (HDACs) play a critical role in gene expression change and RGC cell death in models of optic nerve injury and retinal ischemia (Alsarraf et al., 2014a; Alsarraf et al., 2014b; Biermann et al., 2011; Crosson et al., 2010; Fischer et al., 1970; Schluter et al., 2019). Class I histone HDACs 1, 2, and 3 are upregulated following acute axonal injury, and the HDAC3 isoform translocates from the cytoplasm to the nucleus of RGCs undergoing apoptosis (Pelzel et al., 2010; Pelzel et al., 2012). Targeting of HDAC3 activity in the acute model of optic nerve damage was shown to protect against histone deacetylation, apoptosis, and eventual cell loss in the ganglion cell layer (GCL) (Schmitt et al., 2014; Schmitt et al., 2017). However, targeting HDAC3 activity by reducing its expression does not ameliorate the gene silencing effect post optic nerve injury, indicating a potential role for other class I HDACs in this process. In the DBA/2J mouse model of spontaneous glaucoma, broad-spectrum inhibition of HDACs partially protects against silencing of the ganglion cell specific Fem1c promoter and attenuates cell soma loss, but it does not protect against optic nerve degeneration (Pelzel et al., 2012). Broad-spectrum inhibition of Class I HDACs has been shown to protect RGCs in other models of retinal ganglion cell death (Biermann et al., 2011; Zhang et al., 2012), and HDAC isoform inhibitors are being heavily investigated in models of neurodegeneration (Brochier et al., 2013; Chindasub et al., 2013; Jia et al., 2012; Malvaez et al., 2013; Sun et al., 2007).
Here, we test whether Hdac3 conditional knockout (cKO), or HDAC3-selective inhibition by systemic treatment with RGFP966, elicit therapeutic effects in the DBA/2J spontaneous mouse model of ocular hypertension.
Section snippets
DBA/2J mouse model of ocular hypertension
All mice were handled in accordance with the National Institutes of Health guide for the care and use of laboratory animals (NIH Publications No. 8023, revised 1978), the Association for Research in Vision and Ophthalmology statement for the use of animals for research, and experimental protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Wisconsin-Madison. Mouse cohorts were age-matched and composed of similar numbers of males and females in
Conditional knockout of Hdac3 in the DBA/2J mouse model of spontaneous glaucoma did not protect against BRN3A expression loss, total cell loss or optic nerve degeneration
The DBA/2J model has been well characterized as a mouse model of secondary glaucoma. As the mouse ages, asynchronous RGC loss occurs due to spontaneous increase in ocular hypertension. Ocular hypertension rises in mice beginning at the age of 6 months and progresses to a peak at 10 months of age (Libby et al., 2005a). Peak retinal ganglion cell loss occurs at about 10 months of age (Jakobs et al., 2005; Schlamp et al., 2006). This mouse model has molecular and anatomical features, including RGC
Discussion
Targeting HDAC3 activity in the DBA/2J spontaneous model of glaucoma did not confer dramatic protection against RGC soma degeneration and loss. A conditional knockout of Hdac3 had no significant effect on attenuating cell loss in the GCL. HDAC3 selective inhibition in the DBA/2J.BALBRgcs1 susceptible substrain, however, led to mild but significant protection against total cell loss. The overall protective effect of targeting HDAC3 in the DBA/2J model of glaucoma was dramatically milder than the
Declaration of competing interest
Heather M. Schmitt, None; Joshua A. Grosser, None; Cassandra L. Schlamp, None; Robert W. Nickells, None.
Acknowledgements
This work was supported by National Eye Institute Grant R01 EY012223(RWN) and Vision Science CORE Grant P30 EY016665 (Department of Ophthalmology and Visual Sciences, University of Wisconsin), NRSA T32 grant GM081061, and unrestricted funding from Research to Prevent Blindness, Inc. (Department of Ophthalmology and Visual Sciences, University of Wisconsin).
The authors would like to thank Joel Dietz, UW-Madison Dept. of Ophthalmology and Visual Sciences, for maintenance of the mouse colony and
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