Pathological tau alters head direction signaling and induces spatial disorientation.

Spatial disorientation, an early symptom of dementia, is emerging as an early and reliable cognitive biomarker predicting future memory problems associated with Alzheimer's disease, but the underlying neural mechanisms have yet to be fully defined. The anterodorsal thalamic nucleus (ADn) exhibits early and selective vulnerability to pathological misfolded forms of tau, a major hallmark of Alzheimer's disease and ageing. The ADn contains a high density of head direction (HD) cells, which contribute to spatial navigation and orientation. Hence, their disruption may contribute to spatial disorientation. To test this, we virally expressed human mutant tau (htau) in the ADn of adult mice. HD-tau mice were defined by phosphorylated and oligomeric forms of htau in ADn somata and in axon terminals in postsynaptic target regions. Compared to controls, HD-tau mice exhibited increased looping behavior during spatial learning, and made a greater number of head turns during memory recall, indicative of spatial disorientation. Using extracellular recordings, we identified htau-expressing ADn cells and found a lower proportion of HD cells in the ADn from HD-tau mice, along with reduced directionality and altered burst firing. These findings provide evidence that expression of pathological human tau can alter HD signaling, leading to impairments in spatial orientation.