Research reportInvolvement of mGluR I in EphB/ephrinB reverse signaling activation induced retinal ganglion cell apoptosis in a rat chronic hypertension model
Introduction
Erythropoietin-producing hepatocyte receptors (Ephs) are the largest family of receptor tyrosine kinases (RTKs), which consist of two subtypes, EphA (A1-A10) and EphB (B1-B6). The corresponding ligands are ephrinA (A1-A5) and ephrinB (B1-B3) (Pasquale, 2005, Pasquale, 2008). Ephs and ephrins are reciprocally expressed in two neighboring cells. When ephrin binds to its receptor, bi-directional signals will be generated on receptor-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling), both of which result in tyrosine kinase activation and play important roles in modulating a variety of physiological and pathological processes in the central nervous system (CNS) (Calò et al., 2005a, Calò et al., 2005b, Chen et al., 2012, Dalva et al., 2000, Dong et al., 2015, Ethell et al., 2001, Grunwald et al., 2004, Henderson et al., 2001, Henkemeyer et al., 2003, Hruska and Dalva, 2012, Kania and Klein, 2016, Kayser et al., 2006, Kayser et al., 2008, Klein, 2009, Nolt et al., 2011, Takasu et al., 2002).
Increasing evidence shows that ephrinB/EphB signalings, both forward and reverse, are closely related to retinal ganglion cell (RGC) axon degeneration and neuronal apoptosis in experimental glaucoma models (Dong et al., 2015, Du et al., 2007, Fu et al., 2010, Fu and Sretavan, 2012, Schmidt et al., 2007). In a previous study, we found that EphB/ephrinB reverse signaling was activated in RGCs in a rat chronic ocular hypertension (COH) model, which resulted in RGC apoptosis through increasing the Ca2+-impermeable GluA2-containing AMPA receptor trafficking (Dong et al., 2015). However, it is interesting that Naspm, a selective antagonist of Ca2+ permeable AMPA receptors, only partially blocked EphB/ephrinB reverse signaling activation induced RGC apoptosis, suggesting that other mechanisms may be involved, in addition to AMPA receptors (Dong et al., 2015). It was reported that ephrinB/EphB signaling may directly interact with NMDA receptors and/or metabotropic glutamate receptors (mGluR1) (Calò et al., 2005a, Calò et al., 2005b, Dalva et al., 2000, Grunwald et al., 2004, Takasu et al., 2002). Activation of EphB/ephrinB reverse signaling in rat cultured cortical neurons boosted the NMDA toxicity, which was mediated by mGlu1 receptors (Calò et al., 2005a), thus contributing to excitotoxic neuronal death (Calò et al., 2006, Grunwald et al., 2004). In addition, we have demonstrated that in the physiological condition glutamate endogenously released from bipolar cells increased RGC excitability by activating postsynaptic mGluR I (Li et al., 2017). These studies suggest that mGluR I may be one of key targets when EphB/ephrinB reverse signaling is activated, and over-activation of mGluR I may contribute to RGC apoptosis in COH retina. In the present study, we show that activation of EphB/ephrinB reverse signaling increases RGC excitability in COH retina through interacting with mGluR I, thus increasing RGC apoptosis.
Section snippets
Involvement of activated EphB/ephrinB reverse signaling in intraocular pressure (IOP) elevation induced change of RGC firing
We have previously demonstrated that elevated IOP in COH rats induced an activation of EphB/ephrinB reverse signaling in RGCs (Dong et al., 2015). We first examined whether the activated EphB/ephrinB reverse signaling may change RGC excitability by recording spontaneous firing of RGCs in retinal slices. Since EphB/ephrinB reverse signaling activation in COH rats was observed as early as 1 day (G1d) after IOP elevation (Dong et al., 2015), the recordings were done in retinal slices obtained from
EphB/ephrinB reverse signaling activation induces RGC hyperexcitability in COH retina
Previous studies have demonstrated that neuronal hyperexcitability, which is characterized by the enhanced number of action potentials, is associated with subsequent apoptosis (Ashpole et al., 2012, Pasantes-Morales and Tuz, 2006, Turovsky et al., 2013, Zucchini et al., 2008). In the present study, we found that the frequency of spontaneous firing in RGCs was increased in COH retinas (Fig. 1), which could be mimicked by activating EphB/ephrinB reverse signaling and be blocked by PP2 (Fig. 2,
Animals
All experimental procedures were performed in accordance with the National Institutes of Health (NIH) guidelines for the Care and Use of Laboratory Animals and were approved by the Institutes of Brain Science at Fudan University. Male Sprague-Dawley rats, weighing 100–120 g, obtained from SLAC Laboratory Animal Co., Ltd (Shanghai, China), were housed on a 12 h light/dark schedule.
Rat COH model
COH rats were produced following the procedure previously described in details (Chen et al., 2017, Samsel et al.,
Acknowledgements
We would like to thank Dr. Xiong-Li Yang for his helpful discussion and critical comments on the manuscript. We also thank Dr. David E. Szymkowski (Xencor) for the donation of XPro1595. This work was supported by grants from the National Natural Science Foundation of China (81790642; 31671078; 81430007), and the International Science & Technology Cooperation Program of China (2015DFA31340).
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2020, NeuropharmacologyCitation Excerpt :It should be noted that EphA4 was also expressed in Müller cells (Fig. 3) and intravitreal injection of ephrinA3-Fc induced Müller cell reactivation, as evidenced by the increased GFAP expression (Fig. 10). A number of studies have demonstrated that reactivated Müller cells (gliosis) up-regulated the inflammatory factor release, such as tumor necrosis factor-α (TNF-α), interleukins (IL), and nitric oxide (NO), which induced RGC apoptosis through increasing retinal inflammatory response, oxidative stress, mitochondrial damage, GluA2 trafficking, and neuronal hyperexcitability (Bringmann et al., 2006, 2009; Bringmann and Reichenbach, 2001; Cuenca et al., 2014; Cueva Vargas et al., 2015; Livne-Bar et al., 2016; Tezel et al., 2001; Tezel and Wax, 2003; Zhao et al., 2018). How ephrinA3/EphA4 forward signaling induces Müller cell gliosis will be characterized in our future studies.
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2020, NeuropharmacologyCitation Excerpt :Our results indicate that abnormal expression of mGluR II in the early stage of experimental glaucoma may further increase glutamate concentration in the synaptic cleft by decreasing regulation of glutamate release; this likely promotes RGC apoptosis. In the early stages of glaucoma, both ON- and OFF-type RGCs exhibit a state of hyperexcitability, which is manifested by an increase in spontaneous firing, accompanied by membrane potential depolarization (Risner et al., 2018; Zhao et al., 2018, Fig. 7a and b). An increase in AMPAR-mediated mEPSC frequency was detected in the present study (Fig. 8a and b), which may be due to an increase in the number of synaptic ribbons (Risner et al., 2018) and an increase in glutamate release due to reduced expression levels of mGluR II (Fig. 6b).