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

NEUROBIOLOGY OF DISEASE

卷:149

Article

Tweedy, Clare¹  Kindred, Nathan¹  Curry, Joshua¹  Williams, Christopher¹  Taylor, John-Paul²  Atkinson, Peter³  Randall, Fiona^4,5  Erskine, Daniel²  Morris, Christopheer M.²  Reeve, Amy K.²  Clowry, Gavin J.¹  LeBeau, Fiona E. N.¹ 

[1] Newcastle Univ, Med Sch, Biosci Inst, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[2] Newcastle Univ, Med Sch, Inst Clin & Translat Res, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[3] Eisai Ltd, Eisai Hatfield Res Labs, European Knowledge Ctr, Mosquito Way, Hatfield AL10 9SN, Herts, England

[4] Eisai Inc, Previously Eisai AiM Inst, 4 Corp Dr, Andover, MA 01810 USA

[5] Vertex Pharmacuet Inc, 50 Northern Ave, Boston, MA 02210 USA

关键词: Hippocampus;    Gamma oscillations;    Alpha-synuclein;    Parvalbumin;    Mitochondria;    Burst discharges;   

DOI  :  10.1016/j.nbd.2020.105226

来源: Elsevier

【 摘 要 】

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 (alpha)-synucleinopathies, including dementia with Lewy bodies (DLB) is unclear. To assess this, we used two murine models of DLB that express either human mutant alpha-synuclein (alpha-syn) the hA30P, or human wild-type alpha-syn (hWT alpha-syn) mice. We observed network hyperexcitability in vitro in young (2-5 months), pre-symptomatic transgenic alpha-syn mice. Interictal discharges (IIDs) were seen in the extracellular local field potential (LFP) in the hippo campus in hA30P and hWT-alpha-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 alpha-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 alpha-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 alpha-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 alpha-synucleinopathies such as DLB.