Synaptic and physiological impairments associated with tauopathies in the htau mouse model

Tauopathies are neurodegenerative disorders characterized by pathological accumulation of hyperphosphorylated Tau, a microtubule-associated protein expressed mainly in neurons. Its aberrant hyperphosphorylation reduces affinity for axonal microtubules, promoting accumulation in the somatodendritic compartment. This disrupts synaptic transmission and physiology, promoting neuronal death and neurodegeneration. Glutamatergic neurons appear particularly vulnerable to this Tau-driven dysfunction. We propose analyzing the temporal course of synaptic pathology in the hTau mouse model, performing molecular, histological and electrophysiological analyses. We initially investigated the prefrontal cortex (PFC), which primarily accumulates phospho-Tau leading to cognitive impairments from 6 months of age. Patch-clamp recordings showed decreased firing rate in PFC pyramidal neurons of hTau mice versus wild-type from 3 months of age. Glutamatergic neurons were discriminated using specific reporters to assess progressive Tau accumulation at synaptic terminals via high-resolution immunofluorescence microscopy (Array Tomography). Western blots analyses were used to determine changes in AMPA receptor and phospho-Tau contents in aging hTau PFC synaptosomes. These studies will set the grounds to further evaluate therapeutic strategies preventing synaptic loss in tauopathies. Finally, we will perform cell-type-specific Tau knockdown in the hTau PFC to evaluate its impact on pathology progression.