p53 deficiency increases vulnerability to chronic stress-induced anxiety- and depression-like behaviors: Role of calcium dysregulation and BDNF signaling.

The tumor suppressor protein p53 is a known modulator of neurodegenerative disease (ND) processes. Although p53 expression is increased in the brains of patients with Alzheimer's disease, Parkinson's disease, and ischemic stroke, its role in mood disorders such as anxiety and depression remains unclear. To investigate the role of p53 in behavioral responses to chronic stress, we examined behavioral and molecular alterations in p53 knockout (p53-/-) mice and wild type mice. In p53-/- mice, increased vulnerability to chronic unpredictable mild stress (CUMS)-induced anxiety- and depression-like behaviors was observed following CUMS exposure. In parallel with these behavioral changes, BDNF expression was reduced, whereas glutamate levels were elevated in the prefrontal cortex of p53-/- mice. Increased calcium-associated staining and NMDAR2B expression were observed together with increased neuronal injury- and cell death-related markers. In primary cortical neurons derived from p53-/- mice, corticosterone treatment resulted in greater increases in glutamate levels, NMDAR2B expression compared to wild-type controls. Cell death markers (cleaved caspase-3, p-p38, p-JNK) were upregulated, while neuroprotective signals (BDNF, p-Akt, p-ERK, p-CREB) were suppressed in p53-/- mice, and corticosterone-treated primary neuronal cells from p53-/- mice. These findings indicate that p53 deficiency is associated with enhanced vulnerability to CUMS-induced anxiety- and depression-like behaviors and is accompanied by alterations in calcium handling, glutamate homeostasis, neuronal injury-related markers, and BDNF-associated neuroprotective signaling.