In modern society, diverse stressful environments are recognized as major social problems because they increase vulnerability to psychiatric disorders and depression. Stress responses are mediated by distributed neural circuits, including cortico-limbic and brainstem networks, in which the hypothalamus acts as a central hub regulating circadian rhythms, parental care, and feeding behavior through modulation of neurotransmission. Presynaptic active zone scaffold proteins, including Cytomatrix at the Active Zone-Associated Structural Protein (CAST), are essential for neurotransmitter release, and disruption of their function may contribute to stress-related pathology. Previous studies have reported that CAST knockout (KO) mice exhibit abnormal maternal behaviors and altered sucrose preference, suggestive of depression-like phenotypes. In this study, continuous 24-h home-cage monitoring revealed pronounced restlessness in the locomotor activity of CAST KO mice. Furthermore, the tail suspension test revealed increased immobility in CAST KO mice, consistent with a depression-like state. The administration of a selective serotonin reuptake inhibitor reduced immobility in CAST KO mice, suggesting that CAST deficiency increases susceptibility to depression-like behaviors. Collectively, these findings highlight a critical role for CAST in presynaptic neuromodulator release and in modulating vulnerability to stress-induced depressive behaviors.
