Age dependent changes in neuronal vulnerability and its metabolic substrates

R Medicine > R Medicine (General)

Chitolie, Mark Stephen ; Toescu, Emil

University:University of Birmingham

Department:School of Clinical and Experimental Medicine

关键词: R Medicine;    R Medicine (General);   

Others  :  http://etheses.bham.ac.uk//id/eprint/3737/1/Chitolie12MPhil.pdf

来源: University of Birmingham eTheses Repository

【 摘 要 】

Ageing is an important biological issue affecting all organs in the body. Following from earlier suggestions that the primary neuronal cultures could be aged \(in\) \(vitro\), the first aim of this project was to define the survival and vulnerability of cultured cerebellar granule neurones maintained in culture for < 60 days. Although there was an age-dependent decrease in neuronal number, the remaining neurons were viable. Using this ‘ageing in a dish model’ as a possible \(in\) \(vitro\) model, the project then assessed the age-dependent changes in neuronal vulnerability, particularly in response to glutamatergic stimulation. Overall, with age in culture, there was an increased sensitivity to glutamate that was associated with a larger Ca\(^2\)\(^+\) influx and a greater level of Ca\(^2\)\(^+\) sequestration by the mitochondria. The size of the mitochondrial Ca\(^2\)\(^+\) load was dependent not only upon the amplitude of the Ca\(^2\)\(^+\) signal but also on the length of time that the cytosolic Ca\(^2\)\(^+\) ([Ca\(^2\)\(^+\)]i) remained elevated. Providing that sufficient time was allowed, the mitochondria retained, even in the older neurones, their ability to recover from the elevated Ca\(^2\)\(^+\). This work provides more insight into the underlying mechanisms which contribute to the increase in neuronal vulnerability during the ageing process.