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Title: The role of oxidative stress in age-related changes to ionic currents regulating cerebral giant cells excitability in the pond snail, Lymnaea stagnalis
Author: Hachoumi, Lamia
ISNI:       0000 0004 7427 1014
Awarding Body: University of Brighton
Current Institution: University of Brighton
Date of Award: 2018
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The increase in mean human lifespan since 1900 has been an incredible feat; however, ageing is a challenging issue faced by society. CNS ageing is accompanied by cognitive decline and is the major risk factor for conditions such as Alzheimer’s disease. The understanding of the neuronal ageing process in mammalian species has been significantly hampered due to the complexity of the mammalian brain and restrictions of non-invasive experimental techniques in humans. Many of the changes associated with neuronal ageing are evolutionarily conserved, which raises the possibility of using simpler organisms to investigate this process. This study utilised the pond snail, Lymnaea stagnalis, to perform a top-down analysis of the effects of age on Lymnaea feeding behaviour with a focus on age-related changes to voltage-gated outward currents in an identified pair of neurons, known as the cerebral giant cells (CGCs). The observed decrease in feeding frequency with age was accompanied with reduced spontaneous and evoked CGC firing frequency, an increase in the after-hyperpolarisation, hyperpolarisation of the resting membrane potential and narrowing of action potentials. These changes were associated with underlying alterations to the kinetics and voltage sensitivity of the A-type K+ current. Ageing suppressed a previously uncharacterised voltage-gated outward chloride current and enhanced a newly discovered voltage-gated TEA/4-AP/NPPB insensitive outward current in the CGCs. There were no age-related changes to the conductance of the delayed rectifier or recently identified inward rectifier. The use of selective pharmacological channel blockers inferred that many of the age-related changes to CGC action potential waveform could be explained by the altered A-type K+ current. Ageing of the CGCs was also associated with an increase in MDA and protein carbonyl levels in the CNS, which suggested that oxidative stress might be an important determinant of these changes. Acute exposure to AAPH, a pro-oxidant generator, in young Lymnaea altered feeding frequency and mimicked many of the age-related changes to CGC firing properties that could be prevented or reversed with the antioxidant combination of Vitamins C and E. Furthermore, acute AAPH treatment remarkably replicated the effects of age on the voltagegated outward currents in the young CGCs. In conclusion, this study has characterised the age-related changes to CGC firing properties and has shown that many of these changes can be explained by alterations to the A-type K+ current. These changes can be largely mimicked by acute AAPH treatment in young CGCs, which strongly suggests that oxidative stress is a major driver of CGC ageing.
Supervisor: Yeoman, Mark ; Scutt, Greg ; Patel, Bhavik ; Allen, Marcus Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available