The Role of Forebrain Cholinergic Signalling In Regulating Hippocampal Function And Neuropathology

Cholinergic dysfunction has been associated with cognitive abnormalities in a variety of neurodegenerative and neuropsychiatric disorders, including Alzheimer’s Disease (AD). Cumulative use of drugs with anticholinergic activity is associated with increased risk for dementia and AD. Also, cholinergic function has been implicated in predicting the development of key neuropathological hallmarks seen in AD. However, the relationship between cholinergic dysfunction and conservation of cognitive ability as well as neuronal cell maintenance is not fully understood. Here, we tested how information processing and distinct molecular mechanisms associated with AD are regulated by cholinergic tone in genetically-modified mice in which cholinergic transmission was altered by targeting the vesicular acetylcholine transporter (VAChT), a protein required for acetylcholine storage and release. We assessed the long-term consequences of loss of central cholinergic signalling for hippocampal vulnerability to age-induced stress. We show that deletion of forebrain-specific ACh release leads to age-related increases in neuronal vulnerability, protein aggregation, tau Thr-231 phosphorylation and misfolding, and neuroinflammation. Moreover, inhibition of forebrain cholinergic neurotransmission led to a disturbance in adult hippocampal neurogenesis, highlighted by decreased proliferation and cell survival in neural precursor cells. Additionally, we measured long-term potentiation of Schaffer collateral-CA1 synapses in vivo and assessed information processing by using a mouse touchscreen version of Paired Associates Learning task (PAL). Acquisition in the mouse PAL task was impaired in forebrain-specific VAChT-deficient mice, suggesting a critical role for cholinergic tone. Accordingly, synaptic plasticity in the hippocampus in vivo was disturbed, but not completely abolished, by decreased hippocampal cholinergic signalling. In contrast, spatial memory was relatively preserved. Moreover, we assessed the functional consequence of impaired neurogenesis by testing pattern separation using a Location Discrimination task. Mice with compromised cholinergic signalling were impaired when stimuli were presented with small separation, but not when stimuli were presented with high separation, suggesting that deficient cholinergic tone has major consequences on pattern separation. The pathological changes in the hippocampus we observed in VAChT-deficient mice have important consequences as they presented age-related deterioration in spatial navigation. Our findings provide a refined understanding of the importance of acetylcholine in modulating molecular mechanisms and key cognitive behaviours involved in AD