Abstract
The increase in mean human lifespan since 1900 has been an incredible feat; however, ageingis 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.
| Date of Award | Jun 2018 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Mark Yeoman (Supervisor), Greg Scutt (Supervisor), Bhavik Patel (Supervisor) & Marcus Allen (Supervisor) |