Predominant Role of Serotonin at the Hippocampal Mossy Fiber Synapse with Redundant Monoaminergic Modulation.

The hippocampal mossy fiber (MF) synapse has been implicated in the pathophysiology and treatment of psychiatric disorders. Alterations of dopaminergic and serotonergic modulations at this synapse are candidate mechanisms underlying antidepressant and other related treatments. However, these monoaminergic modulations share the intracellular signaling pathway at the MF synapse, which implies redundancy in their functions. We here show that endogenous monoamines can potentiate MF synaptic transmission in mouse hippocampal slices by activating the serotonin 5-HT4 receptor. Dopamine receptors were not effectively activated by endogenous agonists, suggesting that the dopaminergic modulation is latent. Electroconvulsive treatment enhanced the 5-HT4 receptor-mediated serotonergic synaptic potentiation specifically at the MF synapse, increased the hippocampal serotonin content, and produced an anxiolytic-like behavioral effect in a 5-HT4 receptor-dependent manner. These results suggest that serotonin plays a predominant role in monoaminergic modulations at the MF synapse. Augmentation of this serotonergic modulation may mediate anxiolytic effects of electroconvulsive treatment.