Recently, we have found new signaling pathway involving the serotonin 5-HT7 receptors and matrix metalloproteinase MMP-9 in regulation of synaptic plasticity. We found that 5-HT7R stimulation increases MMP-9 activity Triggering dendritic spines remodeling, synaptic pruning and the impairment of LTP. Our results suggest that 5-HT7-mediated activation of MMP-9 may cause depressive behavior. Interestingly, we have found that also 5-HT4R leads to activation of MMP-9, but in contrary to 5-HT7R leads to maturation of spines and enhancement of LTP. Data indicates that 5-HT4R activation may have an antidepressant effect. In the proposed project we will study detailed mechanism of MMP-9 activation upon 5-HT7R/5-HT4R stimulation and we will investigate how availability of serotonin at the synapse affects MMP-9 activation. We will use advanced techniques based on neuronal culture and fluorescence microscopy. The project may lead to identification of potential targets for new antidepressive drugs.