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Hippocampal network hyperexcitability in young transgenic mice expressing human mutant alpha-synuclein

Lookup NU author(s): Dr Clare Tweedy, Nathan Kindred, Professor John-Paul Taylor, Dr Daniel Erskine, Dr Christopher Morris, Dr Amy Reeve, Dr Gavin Clowry, Dr Fiona LeBeau

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Abstract

© 2020 The AuthorsAbnormal 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.


Publication metadata

Author(s): Tweedy C, Kindred N, Curry J, Williams C, Taylor J-P, Atkinson P, Randall F, Erskine D, Morris CM, Reeve AK, Clowry GJ, LeBeau FEN

Publication type: Article

Publication status: Published

Journal: Neurobiology of Disease

Year: 2021

Volume: 149

Print publication date: 01/02/2021

Online publication date: 20/12/2020

Acceptance date: 16/12/2020

ISSN (print): 0969-9961

ISSN (electronic): 1095-953X

Publisher: Academic Press Inc.

URL: https://doi.org/10.1016/j.nbd.2020.105226

DOI: 10.1016/j.nbd.2020.105226


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