Please use this identifier to cite or link to this item:
Type: Thesis
Title: Aspects of retinal and optic nerve pathology after excitotoxic retinal injury.
Author: Saggu, Sarabjit Kaur
Issue Date: 2011
School/Discipline: School of Medicine
Abstract: A large body of evidence supports the notion that excitotoxicity plays a major role in the pathogenesis of a number of neurological diseases, including central nervous system (CNS) ischaemia, Alzheimer's disease, motor neurone disease, and glaucoma. In the global population 60 years of age and over, these diseases are among the leading causes of mortality and morbidity. Although the site of excitotoxic injury is principally at the level of the cell body (perikaryal), understanding the secondary effects on the neuronal axon is important because axonopathy is a documented early feature of these common neurological conditions; hence, an understanding of the pattern and mechanisms of secondary axonal degeneration after excitotoxic perikaryal injury could provide novel detection and treatment strategies in the early phase of neurological disease. The retina and optic nerve, as approachable regions of the CNS, provide a unique anatomical substrate to investigate axonal degeneration after perikaryal excitotoxic injury. Spatiotemporal changes in the retina and optic nerve were studied after injection of 20nM of Nmethyl-D-Aspartate (NMDA) in the left eye of the rat with the saline-injected right eye serving as the control. Temporal changes in the morphology of retina and optic nerve were studied by light and electron microscopy. Progressive retinal damage beginning at 72 hrs, seen as thinning of the inner retina and cell loss in the ganglion cell layer, showed strong correlation (R= 0.949) with degenerative changes in the optic nerve; the distal optic nerve segment displayed significantly more axon loss, axon swellings and myelin damage than the proximal segment (p<0.05), suggestive of a 'dying-back type degeneration'. Beginning at 24 hrs, electron microscopy demonstrated various features of necrosis in retinal ganglion cells (RGCs): mitochondrial and endoplasmic reticulum swelling, disintegration of polyribosomes, rupture of membranous organelle and formation of myelin bodies. Ultrastructural damage in the optic nerve, which began at 72 hrs, mimicked the changes of Wallerian degeneration, where early nodal-paranodal disturbances were followed by the appearance of three major morphological variants: watery degeneration, dark degeneration, and demyelination. Features suggestive of RGC regeneration in the form of dendritic sprouting after acute excitotoxic injury were also demonstrated at day 7. Immunohistochemistry revealed glial cell responses and changes to the axon transport system. Excitotoxic injury resulted in progressive activation of macroglia (Müller cells and astrocytes) and microglial cells in the retina and optic nerve as demonstrated by increased glial-fibrillary-acidic protein (GFAP) and ED-1 immunolabelling as early as 72 hrs. Interxonal glial cells in the optic nerve also showed increased β-amyloid precursor protein (β-APP) beginning at 72 hrs. Impairment of slow axonal transport at 72 hrs resulted in decrease anterograde transport of neurofilament-light (NF-L) to the axon terminal and hence their accumulation in proximal neuron (seen as NF-L rich spheroids). This fundamental research revealed a pathological picture of Wallerian-like degeneration after perikaryal excitotoxic injury in the CNS. This novel finding is consistent with recent evidence of a labile axonal 'survival' factor, nicotinamide mononucleotide adenylyltransferase 2,(Nmnat2) produced by the neuronal cell body. Further study is required to test the hypothesis that a lack of Nmnat2 is the mechanism by which axons degenerate after excitotoxic perikaryal injury.
Advisor: Casson, Robert James
Blumbergs, Peter Charles
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2011
Keywords: excitotoxicity; retinal ganglion cells; optic nerve; NMDA; light microscopy; ultrastructure; glial cells; axon transport; tunnel staining
Appears in Collections:Research Theses

Files in This Item:
File Description SizeFormat 
01front.pdf419.67 kBAdobe PDFView/Open
02chapters1-9.pdf9.01 MBAdobe PDFView/Open
03chapters10-13.pdf7.43 MBAdobe PDFView/Open

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.