Abstract
Abnormal excitability in cortical networks has been reported in patients and animal models of Alzheimer's disease (AD), and other neurodegenerative conditions. Whether hyperexcitability is a core feature of alpha(α)-synucleinopathies, including dementia with Lewy bodies (DLB) is unclear. To assess this, we used two murine models of DLB that express either human mutant α-synuclein (α-syn) the hA30P, or human wild-type α-syn (hWT-α-syn) mice. We observed network hyperexcitability in vitro in young (2–5 months), pre-symptomatic transgenic α-syn mice. Interictal discharges (IIDs) were seen in the extracellular local field potential (LFP) in the hippocampus in hA30P and hWT-α-syn mice following kainate application, while only gamma frequency oscillations occurred in control mice. In addition, the concentration of the GABAA receptor antagonist (gabazine) needed to evoke IIDs was lower in slices from hA30P mice compared to control mice. hA30P mice also showed increased locomotor activity in the open field test compared to control mice. Intracellular recordings from CA3 pyramidal cells showed a more depolarised resting membrane potential in hA30P mice. Quadruple immunohistochemistry for human α-syn, and the mitochondrial markers, porin and the complex IV enzyme cytochrome c oxidase subunit 1 (COX1) in parvalbumin (PV+)-expressing interneurons showed that 25% of PV+ cells contained human α-syn in hA30P mice. While there was no change in PV expression, COX1 expression was significantly increased in PV+ cells in hA30P mice, perhaps reflecting a compensatory change to support PV+ interneuron activity. Our findings suggest that hippocampal network hyperexcitability may be an important early consequence of α-syn-mediated impairment of neuronal/synaptic function, which occurs without any overt loss of PV interneurons. The therapeutic benefit of targeting network excitability early in the disease stage should be explored with respect to α-synucleinopathies such as DLB.
Highlights
The Lewy body dementias (LBDs), including dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), are together the second most common cause of neurodegenerative dementia after Alzheimer’s disease (AD), accounting for 15–20% of de mentia cases (McKeith et al, 2017)
In DLB aggregated α-syn is widely distributed in the brain including the hippocampus (Adamowicz et al, 2017) but how this leads to the cognitive deficits observed in LBD patients is not understood
We found a lower threshold for Interictal discharges (IIDs) induced by GABAA receptor blockade, and a more depolarised resting membrane potential of cornu ammonis 3 (CA3) pyramidal cells, suggesting both neuronal and network hyperexcitability in hA30P mice
Summary
The Lewy body dementias (LBDs), including DLB and Parkinson’s disease dementia (PDD), are together the second most common cause of neurodegenerative dementia after AD, accounting for 15–20% of de mentia cases (McKeith et al, 2017). In DLB aggregated α-syn is widely distributed in the brain including the hippocampus (Adamowicz et al, 2017) but how this leads to the cognitive deficits observed in LBD patients is not understood. It is unclear how the accumulation of α-syn aggregates impact network activity and neuronal function
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