The effects of CB1R activation on age-related cognitive decline and presynaptic calcium in the aged hippocampus

Higher life expectancy has led to an increasingly ageing population. Healthy ageing is accompanied by a decline in hippocampus-dependent cognitive function, which has detrimental effects on mental health, well-being, and independent living in the elderly population. A recent study using a transgenic mouse line (SyG37) that expresses a calcium sensor at presynaptic terminals, showed an association between the agerelated cognitive decline and elevations in presynaptic calcium in the hippocampus. The endocannabinoid system inhibits presynaptic calcium influx and has recently been demonstrated as a target to reverse age-related hippocampus-dependent cognitive decline in rodents. The mechanism of cognitive function restoration in aged rodents, via activation of the cannabinoid one receptor (CB1R), is not well understood. This thesis aimed to investigate whether cognitive restoration induced by CB1R activation is associated with reversing elevated presynaptic calcium in the aged hippocampus.

Using a combination of in vivo behavioural and pharmacological studies and ex vivo presynaptic calcium imaging in hippocampal slices, this thesis investigated whether chronic CB1R activation reversed cognitive decline and decreased presynaptic calcium levels in the hippocampus using SyG37 mice. Firstly, an altered version of the Barnes maze task was established as a sensitive behavioural paradigm to measure age-related cognitive decline in mice. Next, elevations of presynaptic calcium in the aged hippocampus were confirmed and reduced evoked presynaptic calcium in hippocampal slices were reported following cannabinoid agonist WIN55 application. Subsequently, adult and aged mice were chronically dosed with WIN55 and performed the Barnes maze and object location task. The treatment failed to restore cognitive function. Finally, hippocampal slices were prepared from these mice, and calcium imaging revealed that chronic CB1R activation reduced evoked presynaptic calcium in the aged hippocampus.These results provided evidence for chronic CB1R activation restoring calcium homeostasis in the aged brain, however, this was not associated with reversal of cognitive details.