Purinergic signaling involved in Müller cell function in the mammalian retina

Purines (in particular, ATP and adenosine) act as neuro- and gliotransmitters in the sensory retina where they are involved in bidirectional neuron-glia signaling. This review summarizes the present knowledge about the expression and functional importance of P1 (adenosine) and P2 (nucleotide) receptors in Müller glial cells of the mammalian retina. Mammalian Müller cells express various subtypes of adenosine receptors and metabotropic P2Y receptors. Human Müller cells also express ionotropic P2X₇ receptors. Müller cells release ATP upon activation of metabotropic glutamate receptors and/or osmotic membrane stretching. The osmotic mechanism is abrogated under conditions associated with ischemia-hypoxia and inflammation, resulting in swelling of the Müller cells when the extracellular milieu is hypoosmotic. However, exogenous glutamate, which induces the release of ATP and adenosine, and thus activates P2Y₁ and A₁ adenosine receptors, respectively, prevents such osmotic swelling under pathological conditions, suggesting unimpaired receptor-induced release of ATP. In addition to the inhibition of swelling, which is implicated in regulating the volume of the extracellular space, purinergic signaling is involved in mediating neurovascular coupling. Furthermore, purinergic signals stimulate the proliferation of retinal precursor cells and Müller cells. In normal retinal information processing, Müller cells regulate the synaptic activity by the release of ATP and adenosine. In retinopathies, abrogation of the osmotic release of ATP, and the upregulation of ecto-apyrase (NTPDase1), may have neuroprotective effects by preventing the overactivation of neuronal P2X receptors that are implicated in apoptotic cell death. Pharmacological modulation of purinergic receptors of Müller cells may have clinical importance, e.g., for the clearance of retinal edema and for the inhibition of dysregulated cell proliferation in proliferative retinopathies.     

“Displaced nerve cells” in the human retina

Several kinds of nerve cells in the vertebrate retina can be found in retinal layers other that to which they belong. The present paper discusses all such cells within the human retina, as the author was able to stain them selectively using different neurohistological methods.     

Somatostatin gene expression in the rat retina during postnatal development

目的用分子生物学原位杂交组化法研究视网膜生后发育过程中生长抑素（ｓｏｍａｔｏｓｔａｔｉｎ，ＳＯＭ）基因的表达。方法１０只ＳＤ大鼠分为５组，每组２只，年龄分别为１、２、３、４、８周。原位杂交探针为地高辛标记ＳＯＭ反义ｃＲＮＡ探针。结果１周时，ＳＯＭｍＲＮＡ杂交显色在神经母细胞层内侧及节细胞层，呈弱阳性；２周时，杂交信号逐渐增强，节细胞层呈中等强度染色，内核层为弱阳性；３～４周时，显色明显增加，节细胞层呈深紫色着色，而内核层仍为中等强度染色；８周时成年大鼠，节细胞层阳性细胞散在分布，染色较强，而内核层为弱阳性。结论大鼠出生后，视网膜内ＳＯＭ基因表达逐渐增加，于３～４周时达高峰，至成年时又下降，可能在视网膜生后发育过程中，对视网膜神经元的分化起重要作用。     

Müller cells in the healthy and diseased retina

Müller glial cells span the entire thickness of the tissue, and ensheath all retinal neurons, in vertebrate retinae of all species. This morphological relationship is reflected by a multitude of functional interactions between neurons and Müller cells, including a 'metabolic symbiosis' and the processing of visual information. Müller cells are also responsible for the maintenance of the homeostasis of the retinal extracellular milieu (ions, water, neurotransmitter molecules, and pH). In vascularized retinae, Müller cells may also be involved in the control of angiogenesis, and the regulation of retinal blood flow. Virtually every disease of the retina is associated with a reactive Müller cell gliosis which, on the one hand, supports the survival of retinal neurons but, on the other hand, may accelerate the progress of neuronal degeneration: Müller cells protect neurons via a release of neurotrophic factors, the uptake and degradation of the excitotoxin, glutamate, and the secretion of the antioxidant, glutathione. However, gliotic Müller cells display a dysregulation of various neuron-supportive functions. This contributes to a disturbance of retinal glutamate metabolism and ion homeostasis, and causes the development of retinal edema and neuronal cell death. Moreover, there are diseases evoking a primary Müller cell insufficiency, such as hepatic retinopathy and certain forms of glaucoma. Any impairment of supportive functions of Müller cells, primary or secondary, must cause and/or aggravate a dysfunction and loss of neurons, by increasing the susceptibility of neurons to stressful stimuli in the diseased retina. On the contrary, Müller cells may be used in the future for novel therapeutic strategies to protect neurons against apoptosis (somatic gene therapy), or to differentiate retinal neurons from Müller/stem cells. Meanwhile, a proper understanding of the gliotic responses of Müller cells in the diseased retina, and of their protective vs. detrimental effects, is essential for the development of efficient therapeutic strategies that use and stimulate the neuron-supportive/protective-and prevent the destructive-mechanisms of gliosis.     

A new look at the Bezold-Brücke hue shift in the peripheral retina

Experiments were conducted with a bipartite field to better understand the Bezold-Brücke hue shift in the peripheral retina. The first experiment measured hue shift in the fovea and at 1 degrees and 8 degrees along the horizontal meridian of the nasal retina for nominal test wavelengths of 430, 450, 490, 520 and 610 nm. Peripheral measurements were obtained under two adaptation conditions: after 30 min dark adaptation and following a rod-bleach. Results indicated that foveal hue shifts differed from those obtained after a rod-bleach. Data from the rod-bleach and no-bleach conditions in the periphery were similar, indicating that rods could not account for the differences between the foveal data and the rod-bleach peripheral data. Hue shifts obtained for the 520 nm test stimulus, and to a smaller extent other test wavelengths, at 8 degrees nasal retinal eccentricity revealed that the wavelength of the matching stimulus depended upon the lateral position of the matching and test fields, and this effect was greater in the no-bleach condition than the rod-bleach condition. Several factors were investigated in experiments 2 and 3 to explain the results with the 520 nm test field. It appears that differential rod density under the two half fields and the compression of photoreceptors by the optic disk may partially, but not fully, account for the 520 nm effect.     

Gap junctional coupling in the vertebrate retina: Variations on one theme?

Gap junctions connect cells in the bodies of all multicellular organisms, forming either homologous or heterologous (i.e. established between identical or different cell types, respectively) cell-to-cell contacts by utilizing identical (homotypic) or different (heterotypic) connexin protein subunits. Gap junctions in the nervous system serve electrical signaling between neurons, thus they are also called electrical synapses. Such electrical synapses are particularly abundant in the vertebrate retina where they are specialized to form links between neurons as well as glial cells. In this article, we summarize recent findings on retinal cell-to-cell coupling in different vertebrates and identify general features in the light of the evergrowing body of data. In particular, we describe and discuss tracer coupling patterns, connexin proteins, junctional conductances and modulatory processes. This multispecies comparison serves to point out that most features are remarkably conserved across the vertebrate classes, including (i) the cell types connected via electrical synapses; (ii) the connexin makeup and the conductance of each cell-to-cell contact; (iii) the probable function of each gap junction in retinal circuitry; (iv) the fact that gap junctions underlie both electrical and/or tracer coupling between glial cells. These pan-vertebrate features thus demonstrate that retinal gap junctions have changed little during the over 500 million years of vertebrate evolution. Therefore, the fundamental architecture of electrically coupled retinal circuits seems as old as the retina itself, indicating that gap junctions deeply incorporated in retinal wiring from the very beginning of the eye formation of vertebrates. In addition to hard wiring provided by fast synaptic transmitter-releasing neurons and soft wiring contributed by peptidergic, aminergic and purinergic systems, electrical coupling may serve as the ‘skeleton’ of lateral processing, enabling important functions such as signal averaging and synchronization.     

Calcium-independent release of neurotransmitter in the retina: a “Copernican” viewpoint change

The release of synaptic transmitter in chemical synapses is brought about by Ca²⁺ influx through voltage-dependent Ca²⁺ channels opened by depolarisation of presynaptic terminals. However, in some preparations transmitter release persists or increases in low-Ca²⁺ media, and it has therefore been proposed that transmitter release could also occur through a Ca²⁺-independent, carrier mediated process. In particular it has been suggested that this may be the case for synaptic transmission between photoreceptors and second order neurones of the vertebrate retina. From our recent experiments on synaptic transmission from photoreceptors to horizontal cells of turtle and salamander retinas, it appears that lowering extracellular Ca²⁺ can actually promote Ca²⁺ influx through voltage-activated Ca²⁺ channels via a modification of surface potential of plasma membranes. On the basis of this apparently paradoxical effect of low Ca²⁺ media, it is possible to reaccommodate the so-called Ca²⁺-independent release within the framework of Ca²⁺-dependent synaptic transmission without invoking unconventional mechanisms.     

Development and neurogenic potential of Müller glial cells in the vertebrate retina

Considerable research on normal and diseased states within the retina has focused on neurons. Recent research on glia throughout the central nervous system, including within the retina where Müller glia are the main type of glia, has provided a more in depth view of glial functions in health and disease. Glial cells have been recognized as being vital for the maintenance of a healthy tissue environment, where they actively participate in neuronal activity. More recently, Müller glia have been recognized as being very similar to retinal progenitor cells, particularly when compared at the molecular level using comprehensive expression profiling techniques. The molecular similarities, as well as the developmental events that occur at the end of the genesis period of retinal cells, have led us to propose that Müller glia are a form of late stage retinal progenitor cells. These late stage progenitor cells acquire some specialized glial functions, but do not irreversibly leave the progenitor state. Indeed, Müller glia appear to be able to behave as a progenitor in that they have been shown to proliferate and produce neurons in several instances when an acute injury has been applied to the retina. Enhancement of this response is thus an exciting strategy for retinal repair.     

Carbonic anhydrase XIV identified as the membrane CA in mouse retina: strong expression in Müller cells and the RPE

The presence of carbonic anhydrase (CA) activity in the neural retina has been known for several decades. CA-II, a soluble cytoplasmic isoform expressed by Müller cells and a subset of amacrine cells, was thought to be the sole source of CA activity in the neural retina. However, CA-II deficient mice retain CA activity in the neural retina, which implies that another isoform must be present in that tissue. Recently CA-XIV, an integral membrane protein, was cloned and characterized. We, therefore, sought to determine whether CA-XIV is expressed in the neural retina, and hence is responsible for the CA activity observed in CA-II null animals. Immunohistochemical analyses of histological sections from CA-II null, CA-XIV null, and control mice were performed to localize the CA-XIV isoform, as well as other known retinal markers. Immunoblotting and real-time RT-PCR analyses were also performed to test for CA-XIV expression in retina and other mouse tissues. We determined herein that CA-XIV, a approximately 45kDa membrane protein, is expressed in retina, as it is in kidney. In the retina, CA-XIV is expressed on the plasma membrane of Müller cells. CA-XIV is also found on both the apical and basal membranes of the retinal pigmented epithelium. The data presented here indicate that like CA-II, CA-XIV is highly expressed in the neural retina and, like CA-II, more specifically by the Müller cells. The cellular compartmentalization of the two isoforms in the Müller cell-one cytoplasmic and the other on the plasma membrane-suggest that the two enzymes have specific and unique functions. Future studies will be necessary to assign functions to CA-II and CA-XIV in the mouse neural retina.     

Does cortical motion adaptation exhibit functional properties analogous to light adaptation in the retina?

PURPOSE: The retina codes variations in luminance by adapting to and hence discounting, the mean luminance. During adaptation to a moving pattern, perceived speed decreases. Thus we know that the adapted visual system does not simply code the absolute speed of a stimulus. We hypothesize that adaptation to a moving stimulus serves to optimize coding of changes in speed at the expense of maintaining an accurate representation of absolute speed. In this case we would expect discrimination of speeds around the adapted level to be preserved or enhanced by motion adaptation. METHODS AND RESULTS: After adaptation to motion in the same direction as a subsequent test stimulus, seven of eight subjects showed a reduction of perceived speed in the adapted region and seven showed enhanced discrimination. CONCLUSIONS: We conclude that motion adaptation preserves or enhances differential speed sensitivity at the expense of an accurate representation of absolute speed in a manner analogous to retinal light adaptation.     

Atypical gliosis in Müller cells of the slowly degenerating rds mutant mouse retina

Retinal Müller glial cells are known to undergo reactive changes (gliosis) in various retinal diseases. In virtually all cases studied, an upregulation of glial fibrillary acidic protein (GFAP) and a hypertrophy can be observed. Physiological alterations, such as a strong downregulation of inwardly rectifying K+ (Kir) currents, were found after retinal detachment (man, rabbit) and after ischemia/reperfusion (rat) but not in more slowly progressing retinal degenerations (Borna Disease Virus-infected rats, RCS rats). This led us to hypothesize that Müller cells respond with 'typical' reactive gliosis only to rapid but not to slow retinal degeneration. To test this hypothesis, we studied Müller cells from rds mutant mice (PrphRd2), which show a retinal degeneration of early onset and slow progression, resulting in a complete loss of photoreceptors after 9-12 months. In Müller cells of rds mice, we found immunoreactivity for GFAP, a marker of gliosis in Müller cells, from postnatal day 21 on, accompanied by a moderately increased membrane capacitance (taken as an indicator of hypertrophy), whereas no change in the expression of the Kir4.1 protein occurred in adult rds mice. We failed to observe significant changes in the membrane resistance and the membrane potential of cells from rds mice from first week after birth until 1 year of age. Current densities were decreased in cells from 3- and 5-week old rds mice. Furthermore, as in control cells from wildtype animals, these cells displayed dominant Kir currents, voltage-dependent Na+ currents, and glutamate uptake currents. These data support the idea that in mice as well as previously shown in rats, slow retinal degeneration induces an atypical gliosis of Müller cells.     

Heidelberg retina tomograph in ocular Behçet's disease

PURPOSE: To compare the optic disc topography of patients with ocular Beh?et's disease (BD) with age-matched controls, using Heidelberg retina tomograph (HRT). METHODS: This study included 32 patients (51 eyes) with ocular BD (active and/or inactive), 38 patients (74 eyes) with nonocular BD, and 62 normal subjects (62 eyes). All patients and control group underwent complete ophthalmologic evaluation. Intraocular pressure was less than 22 mmHg in patients and in the control group. The optic nerve heads of all subjects were imaged with the HRT (software 2.01a-M). The following stereometric parameters were calculated for each patient: disc area, cup area, cup/disc area ratio, rim area, height variation contour, cup volume, rim volume, mean cup depth, cup shape measure, mean RNFL thickness, and RNFL cross-sectional area. Differences among the groups were evaluated by Kruskal-Wallis variance analysis. When the Kruskal-Wallis test revealed a significant difference between groups, multiple comparison tests were used to find out which groups differed from which others. RESULTS: The mean disc area was significantly smaller (P<0.05) in patients with ocular and nonocular BD. The mean cup area, mean cup depth, and mean cup volume were significantly smaller (P<0.05) in patients with ocular BD. No significant differences were found between the groups in terms of the other stereometric parameters (P>0.05). CONCLUSION: A small disc and cup may be an additional risk factor for retinal vaso-occlusion in ocular Beh?et's disease.