p53 Knock Out Mice Enhances Anxiety- and Depression-Like Behaviors through an Increase of Glutamate, Calcium, and Cytokine-Mediated Cell Death Signals

Abstract

Extensive epidemiological evidence indicates that patients with certain cancers have a lower probability of developing some types of neurodegenerative diseases (ND) and mood disorders and vice versa. These inverse comorbidities may be associated with several different molecular processes. p53, is a potentially responsible for regulating the development of ND, mood disorders as well as cancers. To investigate whether the tumor suppressor p53 may be associated with ND development, we studied the behavioral changes in p53 knockout (p53−/−) mice and possible action mechanisms. Increased anxiety-like but not depression-like behaviors were displayed in p53−/− mice without impaired motor activities under the non-chronic unpredictable mild stress condition. However, in the p53−/− mice, more anxiety-like and depression-like behaviors were observed in the chronic unpredictable mild stress (CUMS) condition. Our mechanism studies showed that brain-derived neurotrophic factor (BDNF) protein was significantly downregulated, but glutamate levels were significantly increased in the prefrontal cortex of p53−/− mice. Further analyses showed that the p53−/− mice caused more stress-induced nerve damage as a result of an increase in intracellular calcium levels and N-methyl D-aspartate receptor subtype 2B (NMDAR2B) expression. Treatment with corticosterone (mimics CUMS in vitro) increased glutamate levels, NMDAR2B expression, and calcium levels, and these levels were elevated by co-treatment with pifithrin-α (p53 inhibitor) in PC12 cells. Cell death and cell death-mediated signals (p-p38, p-JNK and caspase-3) were upregulated, but neuroprotective signals (BDNF p-Akt, p-ERK and p-CREB) were downregulated in p53−/− mice, and corticoid and/or pifithrin-α treated PC12 cells. These data indicate that p53 may be an important preventive factor against depression and anxiety, and thus suggests a possible correlation between cancer and anxiety/depression development. Running title: Deficiency of p53 enhances mental disorder