Network dysfunction in α-synuclein transgenic mice and human Lewy body dementia

Meaghan Morris, Pascal E. Sanchez, Laure Verret, Alexander J. Beagle, Weikun Guo, Dena Dubal, Kamalini G. Ranasinghe, Akihiko Koyama, Kaitlyn Ho, Gui Qiu Yu, Keith A. Vossel, Lennart Mucke

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13 Scopus citations

Abstract

Objective: Dementia with Lewy bodies (DLB) is associated with the accumulation of wild-type human α-synuclein (SYN) in neurons and with prominent slowing of brain oscillations on electroencephalography (EEG). However, it remains uncertain whether the EEG abnormalities are actually caused by SYN. Methods: To determine whether SYN can cause neural network abnormalities, we performed EEG recordings and analyzed the expression of neuronal activity-dependent gene products in SYN transgenic mice. We also carried out comparative analyses in humans with DLB. Results: We demonstrate that neuronal expression of SYN in transgenic mice causes a left shift in spectral power that closely resembles the EEG slowing observed in DLB patients. Surprisingly, SYN mice also had seizures and showed molecular hippocampal alterations indicative of aberrant network excitability, including calbindin depletion in the dentate gyrus. In postmortem brain tissues from DLB patients, we found reduced levels of calbindin mRNA in the dentate gyrus. Furthermore, nearly one quarter of DLB patients showed myoclonus, a clinical sign of aberrant network excitability that was associated with an earlier age of onset of cognitive impairments. In SYN mice, partial suppression of epileptiform activity did not alter their shift in spectral power. Furthermore, epileptiform activity in human amyloid precursor protein transgenic mice was not associated with a left shift in spectral power. Interpretation: We conclude that neuronal accumulation of SYN slows brain oscillations and, in parallel, causes aberrant network excitability that can escalate into seizure activity. The potential role of aberrant network excitability in DLB merits further investigation.

Original languageEnglish (US)
Pages (from-to)1012-1028
Number of pages17
JournalAnnals of Clinical and Translational Neurology
Volume2
Issue number11
DOIs
StatePublished - Nov 2015

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    Morris, M., Sanchez, P. E., Verret, L., Beagle, A. J., Guo, W., Dubal, D., Ranasinghe, K. G., Koyama, A., Ho, K., Yu, G. Q., Vossel, K. A., & Mucke, L. (2015). Network dysfunction in α-synuclein transgenic mice and human Lewy body dementia. Annals of Clinical and Translational Neurology, 2(11), 1012-1028. https://doi.org/10.1002/acn3.257