AP-1 controls the p11-dependent antidepressant response.

Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed drugs for mood disorders. While the mechanism of SSRI action is still unknown, SSRIs are thought to exert therapeutic effects by elevating extracellular serotonin levels in the brain, and remodel the structural and functional alterations dysregulated during depression. To determine their precise mode of action, we tested whether such neuroadaptive processes are modulated by regulation of specific gene expression programs. Here we identify a transcriptional program regulated by activator protein-1 (AP-1) complex, formed by c-Fos and c-Jun that is selectively activated prior to the onset of the chronic SSRI response. The AP-1 transcriptional program modulates the expression of key neuronal remodeling genes, including S100a10 (p11), linking neuronal plasticity to the antidepressant response. We find that AP-1 function is required for the antidepressant effect in vivo. Furthermore, we demonstrate how neurochemical pathways of BDNF and FGF2, through the MAPK, PI3K, and JNK cascades, regulate AP-1 function to mediate the beneficial effects of the antidepressant response. Here we put forth a sequential molecular network to track the antidepressant response and provide a new avenue that could be used to accelerate or potentiate antidepressant responses by triggering neuroplasticity.

Mapping the physiological and molecular markers of stress and SSRI antidepressant treatment in S100a10 corticostriatal neurons.

In mood disorders, psychomotor and sensory abnormalities are prevalent, disabling, and intertwined with emotional and cognitive symptoms. Corticostriatal neurons in motor and somatosensory cortex are implicated in these symptoms, yet mechanisms of their vulnerability are unknown. Here, we demonstrate that S100a10 corticostriatal neurons exhibit distinct serotonin responses and have increased excitability, compared with S100a10-negative neurons. We reveal that prolonged social isolation disrupts the specific serotonin response which gets restored by chronic antidepressant treatment. We identify cell-type-specific transcriptional signatures in S100a10 neurons that contribute to serotonin responses and strongly associate with psychomotor and somatosensory function. Our studies provide a strong framework to understand the pathogenesis and create new avenues for the treatment of mood disorders.