Presynaptic CAST Deficiency Disrupts Neural Regulation and Promotes Restlessness and Depression-Like Behaviors

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.