It is crucial for the release of neurotransmitters (Strom et al., 1998) as well as for the formation of ribbon synapses, which constitute important contact points between rod-photoreceptors and bipolar cells (Liu X. of wild type (WT I/R) and KO (KO I/R) mice. The left eye served as untreated control (WT CO and KO CO). Scotopic electroretinogram (ERG) recordings were performed to examine rod-bipolar and rod-photoreceptor cell function. Changes of Tnc, rod-bipolar cells, photoreceptors, retinal structure and apoptotic and synaptic alterations were analyzed by immunohistochemistry, Hematoxylin and Eosin staining, Western blot, and quantitative real time PCR. We found increased Tnc protein levels 3 days after ischemia, while Tnc immunoreactivity decreased after 7 days. mRNA expression was comparable in the ischemic retina. ERG measurements after 7 days showed lower a-/b-wave amplitudes in both ischemic groups. Nevertheless, the amplitudes in the KO I/R group were higher than in the WT I/R group. We observed retinal thinning in WT I/R mice after 3 and 7 days. Although compared to the KO CO group, retinal thinning was not observed in the KO I/R group until 7 days. The number of PKC+ rod-bipolar cells, recoverin+ photoreceptor staining and and expression were comparable in all groups. However, reduced rhodopsin protein as well as and mRNA expression levels of rod-photoreceptors were found in the WT I/R, but not in the KO I/R retina. Additionally, a lower number of activated caspase 3+ cells was observed in the KO I/R group. Finally, both ischemic groups displayed enhanced vesicular glutamate transporter 1 (vGlut1) levels. Collectively, KO mice showed diminished rod-photoreceptor degeneration and retinal dysfunction after I/R. Elevated vGlut1 levels after ischemia could be related to an impaired glutamatergic photoreceptor-bipolar cell BAY 293 signaling and excitotoxicity. Our study provides novel evidence that Tnc reinforces ischemic retinal degeneration, possibly by synaptic remodeling. systems to study the molecular mechanisms of ischemic neurodegeneration. Here, the ischemia/reperfusion (I/R) model represents a suitable experimental approach (Hartsock et al., 2016; Schultz et al., 2016; Joachim et al., 2017; Reinhard et al., 2017a; Renner et al., 2017; Palmhof et al., 2019). In the I/R model, retinal ischemia is usually induced by intraocular pressure (IOP) elevation for a definite period of time. Due to the induced high IOP, retinal blood vessels are compressed, which in turn leads to a loss or restriction of blood supply. The ischemic phase is followed by a natural reperfusion phase in which blood circulation is usually restored. This leads to further progressive damage of the retina through oxidative stress. Several studies indicate that ischemic neurodegeneration in the retina of different animal models is characterized by a loss of functional activity and loss of various neuronal subtypes (Kaur et al., 2008; Belforte et al., 2011; Joachim et al., 2012; Minhas et al., 2012; Schmid et al., 2014). I/R injury leads to the death BAY 293 of various retinal neurons, since they are sensitive to hypoxic stress (Kaur et al., 2008; Xu et al., 2015; Hu et al., 2016; Schultz et al., 2016; Palmhof et al., 2019). There is increasing evidence that neurodegenerative processes are accompanied by an extensive remodeling of extracellular matrix (ECM) components (Roll et al., 2012; Roll and Faissner, 2014, 2019). The ECM forms a dynamic meshwork of macromolecules, termed matrisome, which is usually synthesized and secreted by the tissue-embedded cells themselves. Beside structural importance, the ECM regulates fundamental cellular processes such as adhesion, differentiation, migration, proliferation and survival. ECM components include fibrillary proteins, proteoglycans and glycoproteins. Especially, glycoproteins represent important receptor-, adhesion-, and adapter-molecules, which influence extra- BAY 293 as well as intracellular signaling pathways. Particularly, ECM molecules in the retina produce a cellular environment that inhibits neuronal regeneration (Silver, 1994; Reinhard et al., 2015; Pearson et al., 2020). Nevertheless, the functional role of the ECM during ischemic processes and their impact on retinal neurodegeneration is not well known yet. In the present study, we specifically focused on the functional importance of the ECM glycoprotein tenascin-C (Tnc) in retinal ischemia. During early BAY 293 retinogenesis, MAP3K3 Tnc is usually first detectable at embryonic day 13 in post-mitotic cells of the inner neuroblastic layer (Klausmeyer et al., 2007). At this early stage, the knockout (KO) of led to a transient increase of post-mitotic neurons as well as an altered de-differentiation behavior of Mller glia (Besser et al., 2012). In the chicken retina, Tnc was reported to be expressed by horizontal, amacrine and displaced amacrine cells and in close association with the outer plexiform layer (OPL) and inner plexiform layer (IPL) (Bartsch.