1. Relationship between synaptic dysfunction and degeneration in a rodent model of dementia
- Author
-
Meftah, S., Brown, J. T., Witton, J., and Ashby, M. C.
- Abstract
Synaptic degeneration is currently the best biomarker correlate of cognitive decline in dementia. In the years prior to dementia onset, many neurophysiological changes are occurring hypothesised to preserve cognitive function, including alterations in synaptic and neuronal function. This thesis aims to characterise the early synaptic and neurophysiological alterations occurring in a mouse model of tauopathy-driven neurodegeneration (rTg4510). This work was performed in the somatosensory cortex, a well characterised region of the brain in the mouse, which serves as a prototypical model of the neocortex. The work presented in Chapters two and three revealed alterations in synaptic glutamatergic receptor function (reduced NMDA:AMPA receptor ratio) and intrinsic neuronal properties in prodromal tauopathy in rTg4510 mice, using in vitro whole-cell patch clamp electrophysiology. Increased dendritic branching proximal to the soma was seen in these recorded neurons following post hoc imaging of their structure. In more advanced stages of tauopathy, reductions in putative AMPA receptor-mediated spontaneous synaptic activity was observed. Significant reductions in glutamatergic receptor expression and synaptic markers was detected in both prodromal and more advanced tauopathy, quantified from isolated synaptosomes. To characterise how glutamatergic receptor dysfunction manifested in vivo, recording paradigms were optimised for in vivo two-photon targeted whole-cell patch clamp electrophysiology, outlined in Chapter four. This technique was used to simultaneously record subthreshold synaptic properties, network activity, and evoked synaptic responses in the rTg4510 model in early neurodegeneration in Chapter five. Whilst spontaneous network activity was similar between genotypes, there was an observable increase in the fast peak response of evoked activity. This work suggests that synaptic dysfunction is a feature of both prodromal and advanced tauopathy, with different functional and biochemical correlates manifesting at different stages of disease progression. Further characterisation of these processes, and how this contributes to symptomatic decline, can provide a basis to develop novel therapeutic strategies to alleviate tau-mediated synaptic and neuronal dysfunction prior to widespread cell loss.
- Published
- 2021