Age-related changes to ionic currents and excitability in the cerebral giant cells of the pond snail, Lymnaea stagnalis

One of the major issues we will face over the next 50 years is an 'ageing population', and its associated burden of disease and disability. Included in these are the age-related neurological conditions such as Alzheimer's disease, Parkinson's disease and normal brain ageing. Our understanding of how neurones age in mammalian species is hampered by the complexity of the mammalian brain, and the obvious barriers to biophysical measurements from the neurones of humans. With a few possible exceptions, the ageing process is universal across the biosphere. This raises the possibility that studying the nervous system of simpler organisms can help to answer wider questions about age-related changes to mammalian neurones. One such organism is the pond snail Lymnaea stagnalis. The well-defined, and relatively simple feeding network of the Lymnaea Central Nervous System contains a pair of serotonergic modulatory interneurones, the cerebral giant cells (CGCs), which are known to be involved in the learning and memory process. These cells are also known to show age-related changes. The work presented in this thesis provides an insight into the mechanisms that underlie some of these changes. Evidence is provided here that there is a clear reduction in the excitability of the CGCs during ageing: spontaneous firing rate declines, and there is there is an increase in the time course and strength of spike frequency adaptation. Underlying these changes is an age-related increase in a Ca2+ -activated K+ current (IsAHP), an observation consistent with findings in aged hippocampal neurones. Further evidence is provided which suggests that a disruption to Ca2+ homeostasis may drive these changes. In particular there is a reduction in the time constant of recovery from inactivation of voltage gated Ca2+ currents in aged CGCs, along with an increase in the time course of Ca2+ current activation and deactivation. Furthermore, as animals enter very old age, the amplitude of both a nifedipine insensitive, and nifedipine sensitive current increases, along with a shift in voltage sensitivity. Perhaps the most intriguing age-related change however is a switch in the mode of the Na+/Ca2+ exchanger, which forms part of the CGCs' Ca2+ clearance mechanisms. This may underlie an age-related increase in the time course of spike frequency adaptation. Finally, evidence is presented which shows that injection of the IsAHP enhancing drug l-ethyl-2-benzimidazolinone (l-EBIO) into Lymnaea can negatively affect success in an appetitive-learning paradigm, mimicking the aged behavioural phenotype.EThOS - Electronic Theses Online ServiceGBUnited Kingdo