Ischaemia and neurotransmitters in mature and immature white matter
thesisposted on 19.12.2013, 16:09 by Tahani Rajeb Almesmary Mohamed Huria
Optic nerves are an appropriate and widely employed model used to study the function and the pathophysiology of central white matter. This thesis investigates ischaemic injury mechanisms in mature and immature white matter, using isolated adult and neonatal Wistar rat and balb-c mouse optic nerve. A central theme to this work is that both myelinated and nonmyelinated central white matter injury is a partially glutamate-dependent process. Electrophysiology was used to record the compound action potential (CAP) under normal and pathological conditions in both myelinated and premyelinated (post-natal day 2: P2) optic nerves. Following a period of oxygen and glucose deprivation (OGD), both white matters were susceptible to excitotoxicity; mediated by over-activation of N-methyl D-aspartate type glutamate receptors (NMDA-Rs). The previously described higher tolerance of mature mouse optic nerve to OGD was eliminated by exogenous stimulation of NMDA-Rs via direct perfusion with agonists during OGD. My data reconcile earlier contradictions in the literature regarding the significance of NMDA-Rs for ischaemic injury in white matter in the two animals. A second major finding; ischaemic injury in P2 RONs was completely prevented by the NMDARs antagonist MK-801. Interestingly, both MK-801 and a second antagonist, memantine, were toxic to P2 RONs when perfused under control conditions. The presence of NMDA-Rs on premyelinated axons was confirmed by immuno-staining. Neurotransmitters other than glutamate, such as GABA and glycine may also play a role in ischaemic injury of P2, with GABA and glycine receptor block being particularly protective of the CAP against damage. Electron-micrographs of pre-myelinated optic nerve axons and glia confirmed the data collected by electrophysiological recording of the CAP. These findings show that ischaemic damage of immature white matter is mediated largely by NMDA-Rs and that other neurotransmitter receptors also contribute to injury.