Examining the vulnerability of developing white matter to injury

Many neurodegenerative disorders such as Alzheimer’s disease and cerebral ischaemic stroke can be caused by excessive glutamate release. Although experimental models of cerebral ischaemia, using NMDA-R antagonists, have shown protection against acute brain damage clinical trials with such compounds have failed due to the unacceptable side-effects. Firstly, this study aimed to examine the effect of acute exposure to NMDA-R antagonists (MK-801 and memantine) on the ultrastructure features of developing and adult rat optic nerve (RON) using electron microscopy. These data showed that NMDA-R antagonists acutely damage developing white matter (WM), but not the adult WM. In addition, examination of the effect of oxygen glucose deprivation (OGD) on the ultra-structural features of P0 RONs showed a significant reduction in the viability of axons, axon density and a significant increase in glial cell injury. Secondly, this thesis has also examined whether the morphology of white matter is sexually dimorphic in both neonatal and adulthood using RON and corpus callosum. The data from this chapter observed that gender did not affect the white matter (in terms of axon diameter, density, area) at either P0 or adulthood and in addition no gender differences were seen in response to OGD-injury. However, there were some differences in the response to NMDA-R block. Specifically, gender affected axonal density following exposure to MK-801 or memantine – such gender differences were seen at both P0 and adulthood. Thirdly, this thesis investigated the expression of voltage-gated calcium channels (VGCCs) in peripheral axons. The data showed that L-type and P/Q-type channel subunits were present at low levels at P0 and increased by P10 after which they declined by P20. Both double and triple labelling (IHC) experiments demonstrated that Schwann cells express VGCCs during the myelin formation process which starts from around P10.