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The morphology of dendrites constrains and reflects the nature of synaptic inputs to neurons. The visual system has served as a useful model to show how visual function is determined by the arborization patterns of neuronal processes. In retina, light ON and light OFF responding ganglion cells selectively elaborate their dendritic arbors in distinct sublamina, where they receive, respectively, inputs from ON and OFF bipolar cells. During neonatal maturation, the bilaminarly distributed dendritic arbors of ON-OFF retinal ganglion cells (RGCs) are refined to more narrowly localized monolaminar structures characteristic of ON or OFF RGCs. Recently, brain-derived neurotrophic factor (BDNF) has been shown to regulate this laminar refinement, and to enhance the development of dendritic branches selectively of ON RGCs. Although other related neurotrophins are known to regulate neuronal process formation in the central nervous system, little is known about their action in maturing retina. Here, we report that overexpression of neurotrophin-3 (NT-3) in the eye accelerates RGC laminar refinement before eye opening. Furthermore, NT-3 overexpression increases dendritic branch number but reduces dendritic elongation preferentially in ON-OFF RGCs, a process that also occurs before eye opening. NT-3 overexpression does affect dendritic maturation in ON RGCs, but to a much less degree. Taken together, our results suggest that NT-3 and BDNF exhibit overlapping effects in laminar refinement but distinct RGC-cell-type specific effects in shaping dendritic arborization during postnatal development.

Rhodopsin is a G-protein coupled receptor that is expressed exclusively by rod photoreceptors of the retina and is essential for phototransduction and vision. Over 150 missense mutations in rhodops...

Chronic endoplasmic reticulum (ER) stress causes cell death and contributes to disease pathogenesis and progression. ER stress activates intracellular signaling pathways termed the Unfolded Protein Response (UPR). The mechanisms by which chronic ER stress and UPR promote cell death are poorly understood. The PERK arm of the UPR has been implicated in the induction of cell death through its upregulation of proapoptotic CHOP transcription factor. Chop-/- cells are only partially resistant to ER stress-induced apoptosis, and CHOP overexpression alone does not induce apoptosis. These findings strongly suggest that additional mechanisms are involved in regulating cell death downstream of PERK. Here, we find chronic ER stress dramatically suppresses XIAP protein levels. We find that PERK signaling is responsible for suppressing XIAP by eIF2a-dependent translational attenuation and ATF4-mediated proteasomal degradation. PERK’s down-regulation of XIAP occurs independently of CHOP. Loss of XIAP leads to increased ...

In the dystrophic Royal College of Surgeons (RCS) rat retina, there is a progressive loss of photoreceptors. As a result, the retinal circulation becomes apposed to the retinal pigment epithelium (RPE) and neovascular formations develop. RPE and inner nuclear layer cells migrate along these vessels towards the retinal ganglion cell (RGC) layer. The retinal layers gradually become disrupted, and some of the RGC axon bundles involute into the retina. These bundles are always associated with blood vessels, and there is evidence of axon damage where they juxtapose. In wholemount preparations of dystrophic retinae (≥6 months of age), abrupt changes are observed in the trajectory of RGC axon bundles, where they are crossed by circumferential vessels. Degenerative profiles can be seen at these locations. Visualisation of RGCs with Fluoro-gold shows wedge-shaped sectors in the dystrophic retina devoid of labelling, initially in the ventral retina but later spreading dorsally. It is hypothesised that the vessels supplying the neovascular formations contract and pull surface vessels into the retina, thus displacing any axon bundles that lie beneath them into the inner plexiform layer. The contractility may be an intrinsic property of the vessels or it may be conferred by the cells migrating along them. Axonal transport becomes blocked at the points of tension, thereby causing retrograde degeneration of the parent RGCs. Because RGC loss is also a feature of human retinitis pigmentosa, the RCS rat may provide a model to test interventions devised to prevent such loss following photoreceptor degeneration. This model also may be useful for testing methods designed to control blood vessel and matrix formation. J. Comp. Neurol. 392:58–77, 1998. © 1998 Wiley-Liss, Inc.

In viral encephalitis and retinal necrosis, different herpes simplex virus (HSV) strains spread between neurons in the central nervous system (CNS) by distinctly different routes. The steps of viral infection and spread in a single neuron type and nearby glial cells in vivo have been determined for three different strains of HSV (F, H129, and McIntyre-B). The corneas of mice were inoculated with equivalent titers of the strains. Two to 5 days later, the animals were killed. The spread of viral proteins within trigeminal cells was examined using immuno- and electron microscopy and Western blots with anti-HSV polyclonal antiserum. McIntyre-B virus infection resulted in fewer labeled ganglion cells, possibly as a result of reduced viral production in the corneal epithelium or trigeminal ganglion cells. Although the McIntyre-B strain was at least as, if not more efficient, at retrograde transport than the other strains, the amount of McIntyre-B virus that was transported in the trigeminal roots in an anterograde direction was significantly less than the other strains. Uptake by ganglionic satellite cells was qualitatively similar for the three strains, but maturation and release of virus from satellite cells to other neurons were reduced in the McIntyre-B strain. These characteristics may account for the preferential retrograde transneuronal spread of McIntyre-B strain. J. Neurosci. Res. 49:485–496, 1997. © 1997 Wiley-Liss, Inc.

Inoculation of the scarified cornea with herpes simplex virus (type 1) leads to herpetic infection of trigeminal ganglion cells. A recent study of the susceptibility of ganglion cells revealed that there may be at least four populations of trigeminal ganglion cells that are infectable by herpes. Two classes were identified by their neuropeptide content: Substance P or calcitonin gene-related peptide. One class was identified by its affinity for a monoclonal antibody, SSEA-3. The fourth class was recognized by its common affinity for both the monoclonal antibody LD2 and for the lectin Bandeiraea simplicifolia isolectin. However, there has been no direct evidence of which types are infected directly as a result of retrograde transport from the corneal site and which may be infected by cell-to-cell spread. The aim of this study was to determine which classes of neurons, which are known to become infected with HSV after ocular inoculation, supply corneal innervation. We have identified four classes of trigeminal ganglion neurons that supply axons to the central cornea of the mouse, on the basis of their ability to transport Fluoro-Gold retrograde from axons in the central corneal epithelium and stroma. About 40% of the neurons that innervate the cornea contain Substance P or calcitonin gene-related peptide; about 60% of the neurons that innervate the cornea react with the monoclonal antibody SSEA-3. About 36% of all neurons in the whole ophthalmic division react with the LD2 or Bandeiraea simplicifolia isolectin, and Fluoro-Gold labels only 2% of them.(ABSTRACT TRUNCATED AT 250 WORDS)

Rods and cones of the C57BL/6J mouse retina have been examined by light and electron microscopy to distinguish the structural features of the two photoreceptor types. By light microscopy, cone nuclei are conspicuously different from rod nuclei in 1-2 micrometer plastic sections. Cone nuclei have an irregularly shaped clump of heterochromatin that appears in single sections to be one to three clumps, whereas rod nuclei are more densely stained and have one large, central clump of heterochromatin. Cone nuclei make up approximately 3% of the photoreceptor nuclei in both the central and peripheral retina at all ages examined up to 267 days. Cone nuclei are confined to the outer half of the outer nuclear layer, and more than 50% of the cone nuclei lie adjacent to the outer limiting membrane. By electron microscopy, cones in the mouse retina meet virtually every morphological criterion of mammalian cones. The outer segments are conically shaped. Many, if not all of the outer segment discs are continuous with the outer plasma membrane, whereas almost all of the rod discs are not. Cone outer segments are only about half the length of the rod outer segments, and they are contacted by long, villous pigment epithelial cell processes. The cone inner segment diameter is greater than the outer segment diameter, and the accumulation of mitochondria present at the apical end of the inner segment forms a more conspicuous ellipsoid than in rods. The internal fiber or axon of the cone is larger in diameter than that of the rod, and it terminates in a large synaptic pedicle with multiple ribbon synapses, whereas the rod terminal is a smaller spherule with only a single ribbon synaptic complex.

The period of cell genesis of rod and cone photoreceptor cells has been determined in the retinas of C57BL/6J mice. Embryonic mice were exposed to a single dose of 3H-thymidine at embryonic day (E) 10--18 by injecting pregnant mice intraperitoneally. Animals at postnatal ages were injected subcutaneously once between postnatal day (P) 0--10. The eyes were removed at one to three months of age. After fixation, they were embedded in glycol methacrylate, sectioned at 1.5 micrometers and prepared for autoradiographic analysis. All of the cone cells are generated over a relatively short time interval during the fetal period. In the posterior retina, the peak of cone cell genesis occurs at E13-E14, and no cones are generated after E16. The rods, by contrast, are generated later and over a longer time period. They first begin to be generated in the posterior retina on E13, but the peak of cell genesis is not reached until the day of birth, and some rods are generated as late as P5. For both rods and cones the peaks of cell genesis in the peripheral retina occur two to three days later than in the posterior retina. The findings demonstrate that rods and cones are developmentally distinct cell types in the mouse retina.

The Purkinje cell degeneration (pcd) mutant mouse rapidly loses cerebellar Purkinje cells between 3 and 5 weeks after birth and slowly loses retinal photoreceptor cells during the first year of life. In the present study, the retinal degeneration in the pcd mouse was analyzed by light microscopy and autoradiography throughout the first 15 months of age. By day 25 there is an abundance of pyknotic photoreceptor nuclei and many outer segments are clearly disorganized. Thereafter, as the photoreceptor cells are lost, their outer segments slowly become shorter and more variable in length; this slow change in length is explained by an almost proportional reduction in both rod outer segment renewal and disc shedding rates. At about 2 months of age, the rate of rod outer segment renewal is slightly less than half that in littermate controls, and the number of large phagosomes in pigment epithelial cells during the burst of disc shedding soon after light onset is one-half or less than that seen in littermate controls. Between 2 and 10.5 months of age, the retina in the inferior hemisphere of the eye shows substantially more-advanced photoreceptor degeneration than does the superior hemisphere, particularly in the far peripheral retina. A central-to-peripheral gradient of degeneration is conspicuous in the superior hemisphere; a similar but less obvious gradient of degeneration is also seen in the inferior hemisphere of the eye. Loss of photoreceptor cells and their synaptic terminals results in a predictable thinning of the outer synaptic layer. However, the inner nuclear layer shows no measurable thinning and the inner synaptic layer is reduced in thickness by only about 5-15%. Beginning at about 10 months of age, foci of thinned pigment epithelial cells are evident, and by 12 months there is some vascularization of the pigment epithelium by retinal capillaries.

The external potential field along the functionally isolated medullated giant fiber of the shrimp (Penaeus setiferus) was recorded during impulse conduction using 1 M NaCl-filled glass capillary electrodes. The giant fiber displays no nodes of Ranvier, yet shows a conduction velocity greater than 90m/second at 20°C. Recordings from most parts of the myelin-covered giant fiber surface showed only small monophasic positive potentials. However, at the areas of giant fiber-motor giant fiber synapses and where giant fiber axons branch into abdominal ganglia, a small positivity was followed by a negativity (sink of the action current). The local application of action potential depressants to these areas abolished the negativity and converted it into positivity, and consequently impulse conduction was blocked. Application of the action potential depressants to other areas of the giant fiber did not block impulse conduction. The sink of the action current was not found from the axolemma in the myelin cylinder; this part of the axolemma together with the low resistance gap fluid simply serves as a passive current conductor. Light and electron microscopic studies of the two functionally excitable areas revealed the absence of a myelin sheath in some small areas of both regions. Thus, impulse conduction appears to be saltatory, and these excitable areas function as nodes of Ranvier.

The hippocampal formation of newborn mice was explanted and maintained in Maximow culture assemblies for up to 35 days. At the time of explantation, only the suprapyramidal limb of the dentate gyrus was cytoarchitectonically distinct, and electron microscopy of newborn hippocampus revealed no definitive synapses. Histogenesis, as indicated by the development of the infrapyramidal limb of the dentate gyrus, and synaptogenesis, as indicated by the in vitro formation of mossy fiber synapses on the dendrites of hippocampal pyramidal neurons were studied by light and electron microscopy. At 12 days and thereafter in culture, mossy fiber terminals were found in synapsis with dendritic spines probably belonging to pyramidal cells of the hippocampal zone CA4. Near dentate granule cell somata a few axosomatic and many axospinous and axodendritic synapses were found. The data indicate that granule cells of the developing dentate gyrus are capable of differentiation in vitro into a structure essentially equivalent to that developed in vivo. The granule cells may become arranged into a recognizable granule cell layer, and develop dendritic processes which receive synapses virtually identical to those found in the intact organ. The differentiation of these features proceeds in the absence of the extrinsic afferents from the septum or from the contralateral hippocampal formation.