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

Research output: Contribution to journalArticlepeer-review

20 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

Bibliographical note

Funding Information:
This study was supported by a MetLife Foundation Award (to L. M.), a gift from the S.D. Bechtel, Jr. Foundation to the Gladstone Institutes, National Institutes of Health grant K23 AG038357 (to K. A. V.) and P30 NS065780 (to L. M.), a grant from the Alzheimer’s Association (PCTRB-13-288476) made possible by Part the CloudTM (to K.A.V), a grant from the John Douglas French Alzheimer’s Foundation (to K. A. V.), and a University of California, San Francisco AD Research Center pilot-project grant (to K. A. V.). The animal care facility was partly supported by an NIH Extramural Research Facilities Improvement Program Project (C06 RR018928).

Funding Information:
We thank Eliezer Masliah for Thy1-SYN (line 61) transgenic mice and for brain tissues and sections from PDGF-SYN transgenic mice, and helpful discussions; Marie-Francoise Chesselet for Thy1-SYN (line 61) transgenic mice on a pure C57Bl/6J background; Bruce Miller, Alexandra Nelson, and Kate Possin for helpful discussions; Heidi E. Kirsch for EEG interpretation; Srikantan Nagarajan for EEG oversight; Xin Wang, Jing Kang, Daniel Kim, Danielle Mizuiri, and Susanne M. Honma for technical support; the Gladstone Genomics Core for RNA integrity measurements; Mariel Finucane for advice on statistical analyses; John Carroll for advice on preparation of graphics; and Monica Dela Cruz and Amy Cheung for administrative assistance. This study was supported by National Institutes of Health grants K23 AG038357 (to K. A. V.) and P30 NS065780 (to L. M.), a MetLife Foundation Award (to L. M.), a gift from the S.D. Bechtel, Jr. Foundation (to L. M.), a grant from the Alzheimer’s Association (PCTRB-13-288476) made possible by Part the CloudTM (to K.A.V), a grant from the John Douglas French Alzheimer’s Foundation (to K. A. V.), and a University of California, San Francisco AD Research Center pilot project grant (to K. A. V.). The animal care facility was partly supported by an NIH Extramural Research Facilities Improvement Program Project (C06 RR018928).

Publisher Copyright:
© 2015 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

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