Overexpression of the inwardly rectifying potassium channel Kir4.1 or Kir4.1 Tyr9 Asp in Müller cells exerts neuroprotective effects in an experimental glaucoma model.

Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells, which is involved in retinal ganglion cell apoptosis in glaucoma. Modulation of Kir4.

MicroRNA-146a-5p protects retinal ganglion cells through reducing neuroinflammation in experimental glaucoma.

Neuroinflammation plays important roles in retinal ganglion cell (RGC) degeneration in glaucoma. MicroRNA-146 (miR-146) has been shown to regulate inflammatory response in neurodegenerative diseases. In this study, whether and how miR-146 could affect RGC injury in chronic ocular hypertension (COH) experimental glaucoma were investigated.

Dopamine receptor-mediated roles on retinal ganglion cell hyperexcitability and injury in experimental glaucoma.

Extraordinary excitability (hyperexcitability) is closely related to retinal ganglion cell (RGC) injury in glaucoma. Dopamine (DA) and its receptors are involved in modulating RGC excitability. We investigated how DA system affects RGC injury in chronic ocular hypertension (COH) experimental glaucoma model.

Modulation of Rac1/PAK1/connexin43-mediated ATP release from astrocytes contributes to retinal ganglion cell survival in experimental glaucoma.

Connexin43 (Cx43) is a major gap junction protein in glial cells. Mutations have been found in the gap-junction alpha 1 gene encoding Cx43 in glaucomatous human retinas, suggestive of the involvement of Cx43 in the pathogenesis of glaucoma. However, how Cx43 is involved in glaucoma is still unknown.

Activation of retinal glial cells contributes to the degeneration of ganglion cells in experimental glaucoma.

Elevation of intraocular pressure (IOP) is a major risk factor for neurodegeneration in glaucoma. Glial cells, which play an important role in normal functioning of retinal neurons, are well involved into retinal ganglion cell (RGC) degeneration in experimental glaucoma animal models generated by elevated IOP. In response to elevated IOP, mGluR I is first activated and Kir4.

L- and T-type Ca channels dichotomously contribute to retinal ganglion cell injury in experimental glaucoma.

Retinal ganglion cell apoptotic death is the main pathological characteristic of glaucoma, which is the leading cause of irreversible blindness. Disruption of Ca homeostasis plays an important role in glaucoma. Voltage-gated Ca channel blockers have been shown to improve vision in patients with glaucoma.

EphA4/ephrinA3 reverse signaling induced Müller cell gliosis and production of pro-inflammatory cytokines in experimental glaucoma.

Previous work showed that ephrinA3/EphA4 forward signaling contributed to retinal ganglion cell (RGC) damage in experimental glaucoma. Since up-regulated patterns of ephrinA3 and EphA4 were observed in Müller cells and RGCs, an EphA4/ephrinA3 reverse signaling may exist in Müller cells of chronic ocular hypertension (COH) retina. We investigated effects of EphA4/ephrinA3 reverse signaling activation on Müller cells in COH retina.

EphA4/ephrinA3 reverse signaling mediated downregulation of glutamate transporter GLAST in Müller cells in an experimental glaucoma model.

Deficiency of glutamate transporter GLAST in Müller cells may be culpable for excessive extracellular glutamate, which involves in retinal ganglion cell (RGC) damage in glaucoma. We elucidated how GLAST was regulated in rat chronic ocular hypertension (COH) model. Western blot and whole-cell patch-clamp recordings showed that GLAST proteins and GLAST-mediated current densities in Müller cells were downregulated at the early stages of COH.

P2X7/P2X4 Receptors Mediate Proliferation and Migration of Retinal Microglia in Experimental Glaucoma in Mice.

Microglia are involved in the inflammatory response and retinal ganglion cell damage in glaucoma. Here, we investigated how microglia proliferate and migrate in a mouse model of chronic ocular hypertension (COH). In COH retinas, the microglial proliferation that occurred was inhibited by the P2X7 receptor (P2X7R) blocker BBG or P2X7R knockout, but not by the P2X4R blocker 5-BDBD.

Interplay between Müller cells and microglia aggravates retinal inflammatory response in experimental glaucoma.

Background: Glaucoma, the leading cause of irreversible blindness, is a retinal neurodegenerative disease, which results from progressive apoptotic death of retinal ganglion cells (RGCs). Although the mechanisms underlying RGC apoptosis in glaucoma are extremely complicated, an abnormal cross-talk between retinal glial cells and RGCs is generally thought to be involved. However, how interaction of Müller cells and microglia, two types of glial cells, contributes to RGC injury is largely unknown.

Soluble tumor necrosis factor-alpha-induced hyperexcitability contributes to retinal ganglion cell apoptosis by enhancing Nav1.6 in experimental glaucoma.

Background: Neuroinflammation plays an important role in the pathogenesis of glaucoma. Tumor necrosis factor-alpha (TNF-α) is a major pro-inflammatory cytokine released from activated retinal glial cells in glaucoma. Here, we investigated how TNF-α induces retinal ganglion cell (RGC) hyperexcitability and injury.

Rac1 conditional deletion attenuates retinal ganglion cell apoptosis by accelerating autophagic flux in a mouse model of chronic ocular hypertension.

Autophagy has a fundamental role in maintaining cell homeostasis. Although autophagy has been implicated in glaucomatous pathology, how it regulates retinal ganglion cell (RGC) injury is largely unknown. In the present work, we found that biphasic autophagy in RGCs occurred in a mouse model of chronic ocular hypertension (COH), accompanied by activation of Rac1, a member of the Rho family.

Tumor necrosis factor-alpha aggravates gliosis and inflammation of activated retinal Müller cells.

Tumor necrosis factor-alpha (TNF-α), a major inflammatory factor released from activated retinal glial cells, is implicated in the pathogenesis of glaucoma. In this study, we investigated whether and how TNF-α may affect functional conditions of activated retinal Müller cells. Our results showed that in the group I metabotropic glutamate receptor (mGluR I) agonist DHPG-activated cultured Müller cells, TNF-α treatment aggravated cell gliosis, as evidenced by significantly increased expression of glial fibrillary acidic protein (GFAP).

Activated ephrinA3/EphA4 forward signaling induces retinal ganglion cell apoptosis in experimental glaucoma.

Previous studies have demonstrated that EphA4 participates in neuronal injury, and there is a strong interaction between ephrinA3 and EphA4. In this study, we showed that in a rat chronic ocular hypertension (COH) experimental glaucoma model, expression of EphA4 and ephrinA3 proteins was increased in retinal cells, including retinal ganglion cells (RGCs) and Müller cells, which may result in ephrinA3/EphA4 forward signaling activation on RGCs, as evidenced by increased p-EphA4/EphA4 ratio. Intravitreal injection of ephrinA3-Fc, an activator of EphA4, mimicked the effect of COH on p-EphA4/EphA4 and induced an increase in TUNEL-positive signals in normal retinas, which was accompanied by dendritic spine retraction and thinner dendrites in RGCs.

Dopamine D2 Receptor-Mediated Modulation of Rat Retinal Ganglion Cell Excitability.

Ganglion cells (RGCs) are the sole output neurons of the retinal circuity. Here, we investigated whether and how dopamine D2 receptors modulate the excitability of dissociated rat RGCs. Application of the selective D2 receptor agonist quinpirole inhibited outward K currents, which were mainly mediated by glybenclamide- and 4-aminopyridine-sensitive channels, but not the tetraethylammonium-sensitive channel.

Rac1 Modulates Excitatory Synaptic Transmission in Mouse Retinal Ganglion Cells.

Ras-related C3 botulinum toxin substrate 1 (Rac1), a member of the Rho GTPase family which plays important roles in dendritic spine morphology and plasticity, is a key regulator of cytoskeletal reorganization in dendrites and spines. Here, we investigated whether and how Rac1 modulates synaptic transmission in mouse retinal ganglion cells (RGCs) using selective conditional knockout of Rac1 (Rac1-cKO). Rac1-cKO significantly reduced the frequency of AMPA receptor-mediated miniature excitatory postsynaptic currents, while glycine/GABA receptor-mediated miniature inhibitory postsynaptic currents were not affected.

EphrinB/EphB forward signaling in Müller cells causes apoptosis of retinal ganglion cells by increasing tumor necrosis factor alpha production in rat experimental glaucomatous model.

It was previously shown that EphB/ephrinB reverse signaling in retinal ganglion cells (RGCs) is activated and involved in RGC apoptosis in a rat chronic ocular hypertension (COH) model. In the present work, we first show that ephrinB/EphB forward signaling was activated in COH retinas, and RGC apoptosis in COH retinas was reduced by PP2, an inhibitor of ephrinB/EphB forward signaling. We further demonstrate that treatment of cultured Müller cells with ephrinB1-Fc, an EphB1 activator, or intravitreal injection of ephrinB1-Fc in normal rats induced an increase in phosphorylated EphB levels in these cells, indicating the activation of ephrinB/EphB forward signaling, similar to those in COH retinas.

Dopamine D1 receptor-mediated upregulation of BK currents modifies Müller cell gliosis in a rat chronic ocular hypertension model.

Müller cell gliosis is a common response in many retinal pathological conditions. We previously demonstrated that downregulation of Kir channels contributes to Müller cell gliosis in a rat chronic ocular hypertension (COH) model. Here, the possible involvement of outward K currents in Müller cell gliosis was investigated.

Ghrelin Attenuates Retinal Neuronal Autophagy and Apoptosis in an Experimental Rat Glaucoma Model.

Purpose: Ghrelin, a natural ligand for the growth hormone secretagogue receptor type 1a (GHSR-1a), may protect retinal neurons against glaucomatous injury. We therefore characterized the underlying mechanism of the ghrelin/GHSR-1a-mediated neuroprotection with a rat chronic intraocular hypertension (COH) model.

Methods: The rat COH model was produced by blocking episcleral veins.

Neuroprotective effect of 5ɑ-androst-3β,5,6β-triol on retinal ganglion cells in a rat chronic ocular hypertension model.

Previous studies have demonstrated that 5ɑ-androst-3β,5,6β-triol (Triol), a synthesized steroid compound, showed notable neuroprotective effect in cultured cortical neurons. In the present study, we explored whether and how Triol have neuroprotective effect on retinal ganglion cells (RGCs) in a chronic ocular hypertension (COH) rat model. COH model was produced by injecting superparamagnetic iron oxide micro-beads into the anterior chamber, and Triol was administrated (4.

Involvement of the MEK-ERK/p38-CREB/c-fos signaling pathway in Kir channel inhibition-induced rat retinal Müller cell gliosis.

Our previous studies have demonstrated that activation of group I metabotropic glutamate receptors downregulated Kir channels in chronic ocular hypertension (COH) rats, thus contributing to Müller cell gliosis, characterized by upregulated expression of glial fibrillary acidic protein (GFAP). In the present study, we explored possible signaling pathways linking Kir channel inhibition and GFAP upregulation. In normal retinas, intravitreal injection of BaCl significantly increased GFAP expression in Müller cells, which was eliminated by co-injecting mitogen-activated protein kinase (MAPK) inhibitor U0126.

Cannabinoid CB1 and CB2 receptors differentially modulate L- and T-type Ca channels in rat retinal ganglion cells.

Endocannabinoid signaling system is involved in regulating multiple neuronal functions in the central nervous system by activating G-protein coupled cannabinoid CB1 and CB2 receptors (CB1Rs and CB2Rs). Growing evidence has shown that CB1Rs and CB2Rs are extensively expressed in retinal ganglion cells (RGCs). Here, modulation of L- and T-types Ca channels by activating CB1Rs and CB2Rs in RGCs was investigated.

Activation of group I metabotropic glutamate receptors regulates the excitability of rat retinal ganglion cells by suppressing Kir and I .

Group I metabotropic glutamate receptor (mGluR I) activation exerts a slow postsynaptic excitatory effect in the CNS. Here, the issues of whether and how this receptor is involved in regulating retinal ganglion cell (RGC) excitability were investigated in retinal slices using patch-clamp techniques. Under physiological conditions, RGCs displayed spontaneous firing.

Suppression of outward K(+) currents by activating dopamine D1 receptors in rat retinal ganglion cells through PKA and CaMKII signaling pathways.

Dopamine plays an important role in regulating neuronal functions in the central nervous system by activating the specific G-protein coupled receptors. Both D1 and D2 dopamine receptors are extensively distributed in the retinal neurons. In the present study, we investigated the effects of D1 receptor signaling on outward K(+) currents in acutely isolated rat retinal ganglion cells (RGCs) by patch-clamp techniques.

GluA2 trafficking is involved in apoptosis of retinal ganglion cells induced by activation of EphB/EphrinB reverse signaling in a rat chronic ocular hypertension model.

EphB1, expressed in Müller cells, and ephrinB2, expressed in both Müller cells and retinal ganglion cells (RGCs), constitute an EphB/ephrinB reverse signaling in RGCs. Whether and how this reverse signaling is involved in RGC apoptosis in a rat chronic ocular hypertension (COH) model was investigated. In the COH model, both EphB1 and ephrinB2 were significantly increased and the reverse signaling was activated, which was accompanied by increased protein levels of phosphorylated (p) src, GluA2, and p-GluA2.