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Serotonin (5-hydroxytryptoamine, 5-HT) is a neuromodulator in the adult brain, and disorders of 5-HT system are associated with various types of mental illness.Because 5-HT neurons appear early in the embryonic brainstem and send axons diffusely to wide brain regions including the cerebral cortex, it was suggested that 5-HT has neurotrophic activity in the brain development.5-HT has at least 14 receptors, but the roles of each receptor in the brain development are not clear.We examined the roles of 5-HT1A and 5-HT2A receptors in the spine formation and synaptogenesis in the cerebral cortex.Dendritic spines are postsynaptic structures which are formed from filopodia through puncta.We focused on 5-HT1A and 5-HT2A receptors, because these receptors are abundant in the dendrites of cortical neurons from early developmental stages.We cultured cortical neurons of rat embryos up to 14 days and treated them with 5-HT receptor agonists for 24 h.At 15 days in vitro, 5-HT1A agonist decreased the density of puncta and spines, whereas 5-HT2A/2C agonist increased the density of spines with the decrease of filopodia density.Concomitantly, synaptic density was decreased by 5-HT1A agonist, whereas increased by 5-HT2A/2C agonist.In conclusion, the present study shows 5-HT receptors have subtype-specific effects on the spine formation and synaptogenesis.The abnormality of dendritic spines is closely associated with neurodevelopmental disorders and mental retardation.Considering the present study showing that 5-HT regulates the morphology of spines through 5-HT 1A and 5-HT2A/2C receptors, the balance between these receptors may be crucial for the proper maturation of spines.