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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.

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