Abstract
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.
Highlights
Aberrant network excitability has come to the forefront as a significant contributor to cognitive decline in neurodegenerative disorders
After review of several EEG traces from mice of each genotype, we found epileptiform events occurring in A53T and A53T/mTau−/− mice and rare generalized seizures in A53T mice (Figures 1A,B)
The results of this study indicate that endogenous tau is a critical mediator of network hyperexcitability in the A53T mouse model of α-synucleinopathy, even at young ages
Summary
Aberrant network excitability has come to the forefront as a significant contributor to cognitive decline in neurodegenerative disorders. Extended neurophysiological monitoring has revealed that ∼40% of AD patients exhibit epileptiform activity even in the absence of seizures, and this subclinical phenomenon could accelerate disease progression [4]. Myoclonus, another indicator of cortical hyperexcitability that often appears in DLB and cases of familial parkinsonism with dementia, may hasten disease onset [1, 5,6,7]. The role of seizures and epileptiform activity in parkinsonian dementias, remains less well-studied
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