title: Network dysfunction in α-synuclein transgenic mice and human Lewy body dementia.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Gladstone Institute of Neurological Disease San Francisco California 94158; Biochemistry, Cellular and Molecular Biology Graduate Program Department of Biological Chemistry The Johns Hopkins University School of Medicine Baltimore Maryland 21205.
authors.forename: Meaghan
authors.initials: M
authors.lastname: Morris
authors.affiliation: Gladstone Institute of Neurological Disease San Francisco California 94158.
authors.forename: Pascal E
authors.initials: PE
authors.lastname: Sanchez
authors.affiliation: Gladstone Institute of Neurological Disease San Francisco California 94158; Department of Neurology University of California, San Francisco San Francisco California 94158.
authors.forename: Laure
authors.initials: L
authors.lastname: Verret
authors.affiliation: Department of Neurology University of California, San Francisco San Francisco California 94158.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Beagle
authors.affiliation: Gladstone Institute of Neurological Disease San Francisco California 94158.
authors.forename: Weikun
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Neurology University of California, San Francisco San Francisco California 94158.
authors.forename: Dena
authors.initials: D
authors.lastname: Dubal
authors.affiliation: Department of Neurology University of California, San Francisco San Francisco California 94158.
authors.forename: Kamalini G
authors.initials: KG
authors.lastname: Ranasinghe
authors.affiliation: Gladstone Institute of Neurological Disease San Francisco California 94158.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Koyama
authors.affiliation: Gladstone Institute of Neurological Disease San Francisco California 94158.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Ho
authors.affiliation: Gladstone Institute of Neurological Disease San Francisco California 94158.
authors.forename: Gui-Qiu
authors.initials: GQ
authors.lastname: Yu
authors.affiliation: Gladstone Institute of Neurological Disease San Francisco California 94158; Department of Neurology University of California, San Francisco San Francisco California 94158.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Vossel
authors.affiliation: Gladstone Institute of Neurological Disease San Francisco California 94158; Department of Neurology University of California, San Francisco San Francisco California 94158.
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke