Modulation by serotonin 5-HT4 receptors of long-term potentiation and depotentiation in the dentate gyrus of freely moving rats

Tetanization-induced long-term potentiation (LTP) in the hippo-campus can be depotentiated by low-frequency stimulation. 5-HT4 receptors are expressed in the hippocampus and are suggested to be involved in hippocampus-dependent cognitive processes. Since the role of these receptors in the dentate gyrus has yet not been characterized, this study investigated the effects of 5-HT4 receptors on basal synaptic transmission, LTP and depotentiation in the dentate gyrus of freely moving rats. Male Wistar rats were chronically implanted with a recording electrode in the dentate gyrus granule cell layer, a stimulation electrode in the medial perforant path and a cannula for drug administration in the ipsilateral ventricle. The 5-HT4 agonist methoxytryptamine dose-dependently inhibited basal synaptic transmission and LTP. Priming of receptors by a dose of this agonist which elicited no significant change of basal synaptic transmission inhibited depotentiation. These effects could be prevented by the 5-HT4 antagonist RS 39604, which did not produce independent effects on synaptic transmission, LTP or depotentiation. The effects of methoxytryptamine were confirmed with the highly selective 5-HT4 agonist, RS 67333. These results strongly support a role for 5-HT4 receptors in hippocampal synaptic plasticity and provide an important link to findings with regard to the involvement of 5-HT in processes related to learning and memory.