The effect of chronic and acute inflammatory processes on the electrophysiological properties of the basal forebrain cholinergic system, and the interaction between neuronal and glial cell types

Abstract

Ageing and age-related dementias influence every society throughout the world. According to the Australian Bureau of statistics, Dementia is the second leading cause of death of Australians. Dementia is usually referred as a decline in mental ability, inevitably related to loss in cognitive function. Alzheimer's disease (AD), a neurodegenerative disorder characterized by serious impairment in cognitive function and memory, is the most common form of age-related dementia. Several theories exist regarding the etiology of AD. The cholinergic hypothesis is one of the earliest, claiming that the loss of cholinergic neurons in the basal forebrain and the associated loss of cholinergic innervation play a key role in the onset of the disease. However, recent findings suggest that neuroinflammation is a preliminary process, which plays a role in the onset of Alzheimer's disease. The aim of this thesis was to investigate the impact of acute and chronic neuroinflammation on the electrophysiological and anatomical properties of cholinergic and GABAergic neurons in the medial septum during ageing, in three different age groups corresponding to young (4-6 months), adult (9-12 months) and aged (>18 months) animals. The first experimental chapter focused on the impact of normal ageing on the medial septal cholinergic system. Whole cell patch clamp electrophysiological recordings indicated on changes in the intrinsic excitability of both cholinergic and GABAergic neurons during ageing, however, it seems like ageing had a greater impact on cholinergic neurons, supporting the idea of their selective vulnerability during neurodegenerative diseases, such AD. A key finding was that medial septal cholinergic neurons have a biphasic characteristic throughout ageing, as they become more excitable in the 'adult' age group, but their intrinsic excitability drops in the 'aged' group. In the second experimental chapter, we have investigated the impact of acute neuroinflammation on the medial septal cholinergic system and its downstream processes involving cholinergic modulation, such as LTP, in three different age groups. We found that acute neuroinflammation had a differential impact across the different age groups, as it led to an increase in the intrinsic excitability of both young and adult groups, with little effect on neurons from the xiv aged group, abolishing the biphasic alterations in intrinsic excitability seen during ageing. Moreover, extracellular field recordings showed that these alterations affected downstream processes involving cholinergic modulation, such as synaptic plasticity paradigms in the hippocampus. The impact of chronic neuroinflammation was discussed in the third experimental chapter. We investigated the influence of long-term neuroinflammation on the intrinsic properties of GABAergic neurons, as well as synaptic plasticity in the hippocampus during ageing. Our results suggest that chronic neuroinflammation decrease the excitability of GABAergic neurons, and thus increased the overall excitability of the medial septum pathway, causing alterations in the synaptic efficacy. Overall, the data presented in this thesis provides new insights into the differential impact of distinct phases of neuroinflammation on ageing.

Date of Award	2018
Original language	English