Retinal ganglion cell death postponed: giving apoptosis a break?

Glaucoma is characterised by the preferential death of retinal ganglion cells (RGCs). However, mammalian models indicate that neurons pass through a period in which they manifest signs of neuronal damage, but have yet to fully commit to death. Mounting evidence suggests that one of the clearest indications of this process is the reduction in RGC dendritic arborisation, resulting in functional compromise. The extent to which this may be reversible is unclear, since the molecular events that precede changes in dendritic structure have received little attention. Furthermore, there are likely to be many factors involved in this process potentially acting in different individual cells at different times. Recent work in Drosophila shows that dendritic reorganisation/remodelling involves local activation and tight regulation of caspase activity. Here, we propose a model in which the balance between caspases and inhibitors of apoptosis (IAPs) contributes towards the regulation of dendritic remodelling. Thus, RGC dendrite reorganisation and cell death represent opposite ends of a spectrum of events regulated by apoptosis signalling pathways. We summarise relevant events in apoptosis, focusing on caspases and IAPs. We also discuss mechanisms of dendrite development, structure and reorganisation and the implications for early diagnosis and treatment of glaucoma and neurodegenerative disease.

Astroglial plasticity and glutamate function in a chronic mouse model of Parkinson's disease.

Astrocytes play a major role in maintaining low levels of synaptically released glutamate, and in many neurodegenerative diseases, astrocytes become reactive and lose their ability to regulate glutamate levels, through a malfunction of the glial glutamate transporter-1. However, in Parkinson's disease, there are few data on these glial cells or their regulation of glutamate transport although glutamate cytotoxicity has been blamed for the morphological and functional decline of striatal neurons. In the present study, we use a chronic mouse model of Parkinson's disease to investigate astrocytes and their relationship to glutamate, its extracellular level, synaptic localization, and transport. C57/bl mice were treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p). From 4 to 8 weeks after treatment, these mice show a significant loss of dopaminergic terminals in the striatum and a significant increase in the size and number of GFAP-immunopositive astrocytes. However, no change in extracellular glutamate, its synaptic localization, or transport kinetics was detected. Nevertheless, the density of transporters per astrocyte is significantly reduced in the MPTP/p-treated mice when compared to controls. These results support reactive gliosis as a means of striatal compensation for dopamine loss. The reduction in transporter complement on individual cells, however, suggests that astrocytic function may be compromised. Although reactive astrocytes are important for maintaining homeostasis, changes in their ability to regulate glutamate and its associated synaptic functions could be important for the progressive nature of the pathophysiology associated with Parkinson's disease.

The meningeal sheath of the regenerating spinal cord of the eel, Anguilla.

We describe here the meningeal sheath that encloses the spinal cord, and the sheath that develops when the cord regenerates after a total transection. This description is derived from electron and light microscopy. The sheath of the uninjured cord was found to be a single structure of two parts: an outer, thin melanocyte layer and an inner, thicker layer of 2 to 10 rows of fibroblasts, closely associated with collagen and elastic fibers. Soon after cord transection, the injured axons re-grow and, together with the reforming central canal, create a bridge that links the transected cord within 8 days of injury. This bridge is covered at first by a rudimentary meningeal sheath, formed of fibroblasts and macrophages, that later progressively thickens and becomes more compact. By about day 20, the fibroblasts are arranged as 16 to 20 loose rows that include bundles of collagen, oriented along the rostro-caudal axis of the cord. Even after 144 days, the meninx, although substantially thicker than normal because of the numerous fibroblast rows (20 to 30), still lacks the melanocyte layer. In cases in which the meninx at the transection site was mechanically and pharmacologically (6-hydroxydopamine) disrupted, bridge formation was essentially unchanged, and axonal regrowth continued; some regrowing axons, however, extruded from the denuded cord. Accordingly, our findings indicate that although the meningeal sheath is not essential for cord regeneration to take place, it may well facilitate recovery by providing mechanical guidance and support to the regrowing axons.

Reaction of spinal cord central canal cells to cord transection and their contribution to cord regeneration.

After transection, the spinal cord of the eel Anguilla quickly regrows and reconnects, and function recovers. We describe here the changes in the central canal region that accompany this regeneration by using serial semithin plastic sections and immunohistochemistry. The progress of axonal regrowth was followed in material labeled with DiI. The canal of the uninjured cord is surrounded by four cell types: S-100-immunopositive ependymocytes, S-100- and glial fibrillary acidic protein (GFAP)-immunopositive tanycytes, vimentin-immunopositive dorsally located cells, and lateral and ventral liquor-contacting neurons, which label for either gamma-aminobutyric acid (GABA) or tyrosine hydroxylase (TH). After cord transection, a new central canal forms rapidly as small groups of cells at the leading edges of the transection create flat "plates" that serve as templates for subsequent formation of the lateral and dorsal walls. Profile counts and 5-bromo-2'-deoxyuridine immunohistochemistry indicate that these cells are dividing rapidly during the first 20 days of the repair process. The newly formed canal, which bridges the transection by day 10 but is not complete until about day 20, is greatly enlarged (