Structural-functional signatures of early-stage synaptic vulnerability in a mouse model of amyloidosis
File(s)
Author(s)
Melgosa Ecenarro, Leire
Type
Thesis
Abstract
Dysregulation of neuronal circuit activity is increasingly recognized as an early-stage feature of amyloidosis and has been linked to impaired cognition in AD patients. However, the underlying cellular and synaptic changes remain poorly understood, particularly those affecting inhibitory neuronal circuitry. Here, we aimed to identify spatiotemporal patterns of synapse vulnerability and test the relationship to dysregulated cortical activity using a knock-in mouse model of amyloidosis (AppNL-G-F) which expresses a mutated version of the human APP gene under endogenous promoters. First, we conducted an immunofluorescence-based approach to quantify excitatory and inhibitory pre-and post-synaptic markers in the visual, retrosplenial, and entorhinal cortices at 3 and 6 months. We found that VGAT-positive inhibitory pre-synapses display the greatest signs of vulnerability across brain regions and timepoints. Next, we utilized c-Fos-based activity tagging to explore the relationship between synapse vulnerability and excitatory cellular hyperactivity. Our results showed that measures of dendritic spines remained comparable to wild-types, but VGAT puncta were lost at c-Fos-positive cells (both at the dendrite and soma). In addition, VGAT loss correlated with c-Fos intensity, suggesting a potential link between inhibitory pre-synaptic loss and excitatory cellular hyperactivity. Lastly, we conducted longitudinal structural and functional imaging of inhibitory boutons in vivo using two-photon microscopy. Here, we found reductions in bouton size and calcium-mediated activity across different brain states by 3 months in AppNL-G-F mice. However, bouton loss only occurred later at 6 months. Functional weakening of inhibitory boutons was most prominent in regions with high plaque load and predominantly affected boutons exhibiting strong correlations with network activity. Taken together, our assessment of molecular, structural, and functional measures during early-stage amyloidosis highlights the heightened vulnerability of inhibitory pre-synapses, pointing towards their involvement in the emergence of dysregulated cortical activity.
Version
Open Access
Date Issued
2023-07-01
Date Awarded
05/11/2023
License URL
Advisor
Barnes, Samuel
Jackson, Johanna
Sponsor
This work was supported by the UK Dementia Research Institute at Imperial College London, which receives its funding from DRI, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK.
Publisher Department
Department of Brain Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)