The impact of alpha (α)-synuclein pathology on prefrontal cortex networks in a mouse model of Dementia with Lewy Bodies

Abstract

Dementia with Lewy Bodies (DLB) is caused by aggregated insoluble alpha(α) synuclein (α-syn) in neurons and patients exhibit cognitive impairment involving the anterior cingulate cortex (ACC). Cortical network hyperexcitability has also been observed in DLB patients. Parvalbumin interneurons (PVIs) are critical for controlling excitability and normal cognitive function and are often surrounded by a specialised extracellular matrix, the perineuronal nets (PNNs). Loss of PVIs and PNNs occurs in Alzheimer’s Disease but their role in DLB remains unclear. Neuroinflammatory changes may play an early role in DLB. In this thesis, I aimed to investigate hyperexcitability in the early stages of α-syn disease pathology in the ACC using hA30P transgenic mice expressing human α-syn. Changes in PVIs, PNNs, and glial cells in different disease stages were examined. In the A30P mice, I found hyperexcitability in ACC in vitro including frequent seizure-like events associated with PV activity. Additionally, immunofluorescence was conducted to examine the impact of hα-syn pathology on PVIs, PNNs, microglia, and reactive astrocytes in the ACC in young (2-4 months) and aged (10-12 months) A30P and control mice. A trend towards a decrease in the PVI number was revealed in young and aged A30P mice. Additionally, a significantly greater proportion of PNNs surrounding non-PV neurons was observed in young A30P animals. PV somas and PNNs contained hα-syn in young A30P mice and this expression increased with age. Neuroinflammation also increased in all aged animals showing a significant increase in the %area of GFAP+ astrocytes and reactive microglia. This thesis provided evidence of hyperexcitability potentially related to changes in PV neurons in the ACC and a shift in PNN localisation to surround presumed pyramidal neurons in young A30P mice which might be protective against hα-syn pathology. Additionally, the data suggested increased neuroinflammation correlated with age in the ACC in hA30P and control mice.