SUN-025 Chronic Hyponatremia Potentiates Innate Anxiety-Like Behaviors Through the Dysfunction of Monoaminergic Neurons in Mice

Abstract Disclosure: H. Fujisawa: None. N. Iwata: None. M. Hasegawa: None. H. Kubota: None. H. Shoji: None. S. Hattori: None. H. Hagihara: None. Y. Seino: None. A. Mouri: None. T. Miyakawa: None. T. Nabeshima: None. A. Suzuki: None. Y. Sugimura: None. Hyponatremia is the most common clinical electrolyte disorder. Acute hyponatremia can cause neurological complications because of osmotically induced cerebral edema. In contrast to acute hyponatremia, chronic hyponatremia has previously been considered asymptomatic because the brain can successfully adapt to the condition. Recent evidence suggests that chronic hyponatremia may induce neurological manifestations, including psychological symptoms. However, the specific psychological symptoms induced by chronic hyponatremia, the mechanisms underlying these symptoms, and their potential reversibility remain unclear. Therefore, this study aimed to determine whether monoaminergic neurotransmission is associated with innate anxiety-like behaviors potentiated by chronic hyponatremia in a mouse model of chronic syndrome of inappropriate antidiuresis (SIAD). In the present study, we made SIAD model mice by continuously injecting desmopressin, and a liquid diet. These SIAD model mice showed significantly lower serum sodium concentrations (118.1±1.1 mEq/L) compared to the controls (141.0±1.5 mEq/L). Using these mice, we showed that sustained reduction of serum sodium ion concentrations potentiated innate anxiety-like behaviors in the light/dark transition and open field tests. We also found that serotonin and dopamine levels in the amygdala were significantly lower in mice with chronic hyponatremia than in the controls. The turnover of serotonin and dopamine in the amygdala were comparable between the control and chronic hyponatremia groups, suggesting that chronic hyponatremia impairs serotonin and dopamine synthesis. Phosphorylation of extracellular signal-regulated kinase (ERK) in the amygdala was also significantly reduced in mice with chronic hyponatremia, in accordance with previously reported rat and mouse models with potentiated anxiety-like behavior. Notably, after correcting hyponatremia by stopping desmopressin infusion and a liquid diet, increased innate anxiety-like behaviors, decreased serotonin and dopamine levels, and reduced phosphorylation of ERK in the amygdala were normalized. These findings further underscore the importance of treating chronic hyponatremia and demonstrate potential new therapeutic strategies for anxiety in patients with chronic hyponatremia, which will improve their quality of life. Presentation: Sunday, July 13, 2025