Petrache, Alexandra-Loredana; (2021) Investigating cognitive performance and major modulatory inhibitory interneurones in the humanised AppNL-F/NL-F mouse model of Alzheimer’s disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Studies using human AD patients and mouse models of AD have shown abnormal synaptic hyperexcitation, which has been postulated to spread the pathology of AD leading to cognitive deficits. Since neuronal excitation is balanced by specialised inhibitory interneurones, we hypothesise that major inhibitory interneurones are disrupted in AD, could cause this imbalance and contribute to cognitive worsening. This study focused on three modulatory inhibitory interneurones that express cholecystokinin (CCK), somatostatin (SST) and a subtype that expresses calretinin (CR) and that are specialised to only contact other interneurones. The focus was on the CA1 hippocampal region in the AppNL-F/NL-F mouse model and age-matched wild-type mice. A top-down approach was taken to first investigate symptoms of AD such as memory impairment and anxiety with the T-arm maze and novel object recognition, and open arena, respectively. This was followed by investigation of anatomical interneurone and pyramidal cell density using immunohistochemistry and confocal microscopy, and the expression of α5-containing GABAA receptor subunit, which is important in memory formation. These parameters were correlated with typical hallmarks of AD such as amyloid-β (Aβ) accumulation and gliosis- proliferation of astrocytes and microglia. The results indicate modest memory impairment in the AppNL-F/NL-F starting at 6-9 months and continuing to 18-22 months, accompanied by indicators of anxiety. Furthermore, in the AppNL-F/NL-F model, Aβ selectively infiltrated CCK and SST cells, but not CR cells. This was associated with age-dependent CCK and SST cell density decline, in contrast with the preserved CR cells. A closer look at receptor expression showed that all three interneuron subtypes in wild-type and AppNL-F/NL-F animals, as well as pyramidal cells, expressed the α5 subunit. The results highlight selective interneurone destruction in disease, accompanied by AD hallmarks and cognitive deficits. The widespread expression of the α5 subunit on multiple cell types emphasises its importance in disease.

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