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.