AMPA receptors: Role in brain injury

Fowler, Jill H (2003) AMPA receptors: Role in brain injury. PhD thesis, University of Glasgow.

Abstract

Glutamate can be considered a 'Jekyll and Hyde' molecule that serves an essential role as neurotransmitter whilst having potentially damaging, neurotoxic effects. The neurotransmitter and neurotoxic properties of glutamate are partly mediated by AMPA receptors. Due to their ubiquitous distribution in the central nervous system (CNS), events occurring at the AMPA receptor can have profound consequences for CNS functioning. In this thesis, two AMPA receptor-mediated events were examined. Firstly, the neurotoxic potential of AMPA receptor-mediated excitotoxicity was examined in white matter. Secondly, AMPA receptor potentiators, which enhance glutamatergic neurotransmission, were investigated. The role of AMPA receptors in mediating axonal damage in vivoWhite matter is vulnerable to injury in a variety of neurological disorders, however, comparatively less is known about the mechanisms of white matter injury compared to grey matter injury. In addition to their presence on neuronal perikarya, AMPA receptors are present on the cellular components of white matter. To determine if axons were vulnerable to AMPA receptor-mediated excitotoxicity in vivo, AMPA (2.5 or 25 nmol) or vehicle was injected into the subcortical white matter of rats. AMPA induced a dose dependent increase in axonal damage assessed with MAP 5 immunohistochemistry. In addition, AMPA induced myelin, oligodendroglial and neuronal damage. The AMPA-induced damage was attenuated by pre-treatment with the AMPA receptor antagonist SPD 502 (16mg/kg), but not with co-administration of the NMDA receptor antagonist (MK 801, 5nmol); suggesting that it occurs through AMPA-receptor mediated mechanisms. The role of AMPA receptor-mediated excitotoxicity in mediating axonal damage following focal cerebral ischaemia was also examined. In addition to protecting grey matter damage, pre-treatment with the AMPA receptor antagonist SPD 502 (16mg/kg) significantly reduced axonal damage following middle cerebral artery occlusion. Collectively, these data suggest a role for AMPA receptors in mediating both grey and white matter damage, and suggest that AMPA receptor antagonists are capable of salvaging multiple cellular elements required for the functioning of the CNS.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Jim McCulloch
• Keywords: Neurosciences
• Date of Award: 2003
• Depositing User: Enlighten Team
• Unique ID: glathesis:2003-74227
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 23 Sep 2019 15:33
• Last Modified: 23 Sep 2019 15:33
• URI: https://theses.gla.ac.uk/id/eprint/74227