Involvement of protein kinase C beta1-serotonin transporter system dysfunction in emotional behaviors in stressed mice

Selective serotonin reuptake inhibitors are the first-line antidepressants for treating major depressive and post-traumatic stress disorders. These inhibitors directly bind to the serotonin transporter (SERT). Protein kinase C (PKC) is a key regulator of SERT functions as it can attenuate SERT activity through phosphorylation and its subsequent internalization. However, whether PKC-regulated SERT functions are involved in emotional impairment in a mouse model of stress remains unclear. Using a mouse model of swim-induced stress, we investigated whether the PKC-SERT system is involved in emotional impairment and tried to identify the PKC isoforms involved in this mechanism. Mice exposed to swim stress showed enhanced immobility and decreased social interaction times compared to those in swim stress-naive mice. Moreover, significant decreases in phosphorylated PKCβI and SERT levels were observed in the prefrontal cortex of stressed mice compared to those of swim stress-naive mice. No changes in levels of other phosphorylated PKC isoforms were observed between the two groups. Phorbol 12-myristate 13-acetate (a PKC activator) administration significantly attenuated enhanced immobility and decreased social interaction time in stressed mice and increased the serotonin turnover. Further, the PKC activator increased levels of phosphorylated PKCβI or SERT and decreased cell surface localization of SERT in stressed mice. Contrary to this, chelerythrine (a PKC inhibitor) administration exacerbated the immobility and sociality of mice exposed to mild stress. Our results suggest that PKCβI activation attenuates emotional impairment by suppressing SERT function in stressed mice. Thus, PKCβI may be a key target for the development of new treatment strategies for emotional impairment in stress-related disorders.