Significance
Exposure to stressful events is a well-known inducer of neuronal atrophy implicated in the development of neuropsychiatric and neurological pathologies (e.g., depression and Alzheimer’s disease), although the underlying molecular mechanisms remain elusive. The current study demonstrates that absence of the cytoskeletal protein Tau blocks stress-evoked hippocampal synaptic signaling and morphofunctional damages related to both neuronal structure and connectivity as well as subsequent behavioral deficits. These findings suggest, for the first time to our knowledge, that Tau protein is a key regulator of neuronal malfunction found in stress-driven hippocampal pathology.
Abstract
Exposure to chronic stress is frequently accompanied by cognitive and affective disorders in association with neurostructural adaptations. Chronic stress was previously shown to trigger Alzheimer’s-like neuropathology, which is characterized by Tau hyperphosphorylation and missorting into dendritic spines followed by memory deficits. Here, we demonstrate that stress-driven hippocampal deficits in wild-type mice are accompanied by synaptic missorting of Tau and enhanced Fyn/GluN2B-driven synaptic signaling. In contrast, mice lacking Tau [Tau knockout (Tau-KO) mice] do not exhibit stress-induced pathological behaviors and atrophy of hippocampal dendrites or deficits of hippocampal connectivity. These findings implicate Tau as an essential mediator of the adverse effects of stress on brain structure and function.
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