Soluble tau aggregates decrease the threshold for thalamic oscillations and increase the excitability of thalamic neurons

Abstract

Sleep disturbances frequently occur early in dementias such as Alzheimer's disease (AD) and potentially arise from many factors including cortico-thalamo-cortical (CTC) loop dysfunction. It has been reported that tau filament deposition occurs in the thalamus and there is thalamic atrophy in symptomatic AD patients which could contribute to CTC loop disturbance. Here we have investigated whether human recombinant tau soluble aggregates can induce dysfunction in thalamic circuits. Electrophysiological measurements were made from acutely isolated male and female rat corticothalamic slices following incubation with tau aggregates. Tau aggregates markedly reduced the threshold for inducing spindle-like oscillations and increased the excitability of thalamic neurons. Tau aggregates also significantly enhanced the frequency of miniature excitatory postsynaptic currents recorded in ventrobasal thalamic neurons, suggesting possible changes in terminal Ca²⁺ influx. These pro-excitatory effects of tau aggregates could contribute to the aberrant CTC loop dysfunction observed in AD models and patients, which manifests as sleep disturbances and absence seizures.