Abnormal intraneuronal accumulation of the presynaptic protein α-synuclein (α-syn) is implicated in the etiology of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). Recent work revealed that mice expressing human α-syn with the alanine-53-threonine (A53T) mutation have a similar phenotype to the human condition, exhibiting long-term potentiation deficits, learning and memory deficits, and inhibitory hippocampal remodeling, all of which were reversed by genetic ablation of microtubule-associated protein tau. Significantly, memory deficits were associated with histological signs of network hyperactivity/seizures. Electrophysiological abnormalities are often seen in parkinsonian dementias. Baseline electroencephalogram (EEG) slowing is used as a supportive diagnostic feature in DLB and PDD, and patients with these diseases may exhibit indicators of broad network dysfunction such as sleep dysregulation, myoclonus, and seizures. Given the translational significance, we examined whether human A53T α-syn expressing mice exhibit endogenous-tau-dependent EEG abnormalities, as measured with epidural electrodes over the frontal and parietal cortices. Using template-based waveform sorting, we determined that A53T mice have significantly high numbers of epileptiform events as early as 3–4 months of age and throughout life, and this effect is markedly attenuated in the absence of tau. Epileptic myoclonus occurred in half of A53T mice and was markedly reduced by tau ablation. In spectral analysis, tau ablation partially reduced EEG slowing in 6–7 month transgenic mice. We found abnormal sleeping patterns in transgenic mice that were more pronounced in older groups, but did not find evidence that this was influenced by tau genotype. Together, these data support the notion that tau facilitates A53T α-syn-induced hyperexcitability that both precedes and coincides with associated synaptic, cognitive, and behavioral effects. Tau also contributes to some aspects of EEG slowing in A53T mice. Importantly, our work supports tau-based approaches as an effective early intervention in α-synucleinopathies to treat aberrant network activity.
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We are grateful for the diligent animal care provided by Research Animal Resources and veterinary staff at the University of Minnesota. The expertise of Helen Scharfman, Korey Kam, and Simon Gray was instrumental in this work's completion, and we thank them for their guidance in EEG signal processing and data analysis, as well as provision of Spike2 scripts. We thank Nisha Venkateswaran for aiding in the development and implementation of a seizure detection protocol, as well as for support during animal surgeries and recordings. We thank Stephen Martin for assisting in processing of spectral data. Lastly, we thank Balvindar Singh and H?ctor Martell-Mart?nez for thoughtful discussion and coordinating the transfer of animals. Funding. This work was supported by NIH grants R01 AG058820 (KV), R56 NS113549 (ML and KV), R01 NS086074 (ML), R01 NS092093 (ML), R01 108686 (ML), and R01 AG044342 (ML), the Rotary International Coins for Alzheimer's Research Trust (KV), and funds from the Institute for Translational Neuroscience at the University of Minnesota (KV).
© Copyright © 2020 Peters, Fahrenkopf, Choquette, Vermilyea, Lee and Vossel.
- Parkinson's disease
- dementia with Lewy bodies
PubMed: MeSH publication types
- Journal Article