The promnesic effect of G-protein-coupled 5-HT4 receptors activation is mediated by a potentiation of learning-induced spine growth in the mouse hippocampus

Pharmacological modulation of synaptic efficacy is a prominent target in the identification of promnesic compounds. Here, we report that pretraining administration of the serotonin 5-HT₄ receptors (5-HT₄Rs) partial agonist SL65.0155 enhances simultaneous olfactory discrimination performance and potentiates learning-induced dendritic spine growth in the mouse hippocampus. SL65.0155 does not affect spine density in the pseudo-trained mice and, by itself, does not promote spine growth. Injecting the 5-HT₄ antagonist RS39604 prior to SL65.0155 prevents both the increase in performance and the additional formation of spines, thus confirming the 5-HT₄Rs specificity of the observed effects. These findings provide evidence that 5-HT₄Rs stimulation selectively increases experience-dependent structural plasticity in learning-activated hippocampal circuits.