Note:

Thesis (M. Phil.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 78-112).

No description available.

Afhandling - Copenhagen.

No description available.

Optic Nerve Hypoplasia (ONH) is the leading cause of childhood blindness in developed nations and its prevalence has been rising. Yet, we know little about the genetic, molecular, or cellular mechanisms underlying ONH. A previous study described ONH in a cohort of patients with mutations in CASK, an X-linked gene with established roles in neural development and synaptic function. I have demonstrated that heterozygous deletion of CASK in mice (Cask+/-) recapitulates many of the phenotypes observed in patients with CASK mutations, including ONH. This includes reduced optic nerve size, reduced numbers of retinal ganglion cells (RGCs), reduced RGC axonal diameter, and deficits in vision-related tasks. Further analysis on a homozygous partial loss of function variant (Caskfl/fl) also displayed ONH with reduced numbers of RGCs. In order to understand the mechanisms underlying CASK-associated ONH, I explored whether RGCs, the projection neurons of the retina and the cells whose axons comprise the optic nerve, generate CASK. Indeed, mRNA analysis revealed expression of CASK by a large cohort of RGCs. In order to assess whether loss of CASK from a majority of RGCs leads to ONH, I crossed a conditional allele of CASK (CASKfl/fl) with transgenic mice that express Cre Recombinase (Cre) in RGCs. Deletion of CASK from RGCs did not further alter ONH size nor RGC survival. These results demonstrate that loss of CASK signaling in this discrete neuronal populations is not sufficient to lead to further disruption in the assembly of the subcortical visual circuit, suggesting a non-cell autonomous mechanism for loss of CASK in ONH. / Doctor of Philosophy / The connection between the eye and the brain is crucial for successful vision. Impairment of this connection by either loss of the retinal neurons that project axons to the brain or damage to the nerve (optic nerve) lead to blindness. This occurs in a disease called Optic Nerve Hypoplasia (ONH), which is the leading cause of childhood blindness in developed countries. Discovering the risk factors associated with this disease and mechanisms underlying the disease can help us build tools to treat and repair the optic nerve. Previously, mutations in the CASK gene were found in patients with ONH. Here, I developed a mouse model of CASK mutations to phenocopy the human patients, and used this model to explore the development of ONH. For example, with this mouse model I described for the first time, the timeline of disease progression. Surprisingly, I also showed that loss of CASK specifically from the neurons whose axons generate the optic nerve did not lead to ONH, suggesting that ONH may develop from a failure of a network of cells, rather than just one population of cells.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

The effects of certain NSAIDs were determined on agonist-evoked responses recorded from rat neurones maintained in vitro using electrophysiological techniques. Initially, the rat isolated vagus and optic nerves were employed. Alphaxalone, pentobarbitone, propofol and the NSAID, mefenamic acid (MFA), potentiated GABA-evoked responses of the vagus nerve. Propofol (1-100µM) selectively potentiated GABA and glycine-evoked responses of the rat vagus and optic nerves, but had little effect on nicotinic acetylcholine-, a,β-methylene-ATP or 5-hydroxytryptamine-mediated responses. The interaction between MFA and ligand-gated receptors was investigated further using voltage-clamped rat hippocampal neurones maintained in culture. MFA (3-100µM) selectively, concentration-dependently and reversibly potentiated GABA-evoked responses, consistent with the observations made using the vagus nerve. MFA (3-100|aM) however had little or no effect on glycine, AMPA, kainate or NMDA-receptor mediated responses. A final series of experiments investigated the site and molecular mechanism of the interaction between MFA and the GABA-gated chloride ion channel. The potentiating effects of MFA (and other fenamates) were not the result of prostaglandin synthesis inhibition, since other NSAIDs did not modulate the GABA(_A) receptor (GR). The actions of MFA were not mediated via the benzodiazepine site of the GR, nor where they due to inhibition of GABA- uptake or membrane perturbation. The modulatory effects of MFA were not use-dependent, but the potentiating effects of MFA were voltage-dependent, where the potentiation was 3-fold greater at -100mV than at +40mV, with no change in the equilibrium potential for GABA. MFA activated a current, in the absence of GABA. Hippocampal neurones varied in sensitivity to modulation by MFA and the anticonvulsant, loreclezole, which may indicate a degree of sub- unit selectivity. These data are discussed in relation to the possible site and mechanism of action of fenamates at the GR, their similarities with other positive modulators of the GR and the neurophysiological implications of these findings.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Reorganization of the intermediate filament (IF) network during axonal regeneration is accompanied by changes in the expression of various IF proteins. An increase in expression of the neuronal IF subunit gefiltin in goldfish retinal ganglion cells (RGCs) has been linked to the unique ability of the goldfish optic nerve to regenerate following injury. Evidence suggests that the optic tectum may regulate the expression of gefiltin during regeneration. The goal of this thesis was to determine the function of the tectum in the regulation of gefiltin mRNA expression during optic fiber regeneration in the goldfish. It was found that gefiltin mRNA levels in the RGCs of animals that received an optic nerve crush (ONC group) increased by 10 days, peaked from 20 to 38 days at around 5.5-fold over normal, and declined to near normal by 115 days. In animals that had the entire tectum removed and an optic nerve crush (ETR group), gefiltin mRNA levels increased by 10 days, peaked at 20 days at around 5.5- to 6.5-fold over normal, and although they dropped slightly thereafter, they remained elevated at around 5-fold over normal for at least 115 days. When axons regenerated to the ipsilateral tectal lobe as a result of a left tectal lobe removal and left eye removal surgery the expression pattern of gefiltin mRNA paralleled that of the ONC group. It was also found that the abundance of gefiltin subunits in the retina was elevated at 30 days of regeneration in ONC and ETR animals, and that levels in the nerve were reconstituted to 80% of normal by 30 days. These results demonstrate that increases in gefiltin mRNA and protein levels during optic nerve regeneration are independent of the tectum, whereas the downregulation of gefiltin mRNA levels is entirely dependent upon the tectum. (Abstract shortened by UMI.)