The neurotransmitter serotonin (5-HT) plays a pivotal role in the regulation of multiple events in the CNS. Recently we demonstrated that in mouse hippocampal neurons, activation of endogenous 5-HT7 receptors significantly increased neurite length, whereas stimulation of 5-HT4 receptors led to a decrease in the length and number of neurites. We showed that the 5-HT4 receptor is coupled not only to the heterotrimeric Gs, but also to G13 protein. Activation of this signaling pathway results in RhoA-mediated modulation of gene transcription and in reorganization of the actin cytoskeleton. We also demonstrated that serotonin receptor 5- HT7 can activate heterotrimeric G12 protein, leading to the selective activation of small GTPases RhoA and Cdc42. Agonist-dependent activation of the 5-HT7 receptor induced pronounced filopodia formation via a Cdc42- mediated pathway paralleled by RhoA-dependent cell rounding. This molecular model for 5-HT4 and 5-HT7 receptor mediated signalling provides a link between receptor activation and a subsequent change in morphology. Our recent studies confirmed a direct link between 5-HT7 receptor activation and an increase in synaptogenesis as well as modulations in synaptic plasticity in hippocampal neurons. As the molecular model suggests an opposing role for the 5-HT4 receptor in morphology we investigate in this study whether 5-HT4 receptor activation leads to changes in synaptogenesis (formation of presynaptic clusters , filopodia, spines), spontaneous synaptic activity in primary culture of mouse hippocampal neurons as well as in synaptic plasticity. Additionally we study changes in long-term potentiation related to the 5-HT4 receptor activity in organotypic cell culture. Our data suggests that serotonin plays a prominent role in regulating the neuronal cytoarchitecture and synaptic plasticity in addition to its classical role as a neurotransmitter.