Pathway- and region-specific serotonergic modulation in the dentate gyrus

Serotonin (5-hydroxytryptamine; 5-HT) is a neuromodulator that plays essential roles in regulating emotional behavior and hippocampal information processing. Although serotonergic fibers in the hippocampus are thought to affect dentate gyrus activity mainly through modulation of inhibitory interneurons in the hilus, we previously reported that exogenous 5-HT can suppress lateral perforant path inputs to granule cells via 5-HT_1A and 5-HT₂ receptors, even in the presence of GABA_A receptor blockade. In the present study, we used whole-cell patch-clamp recordings in acute hippocampal slices to examine whether endogenous 5-HT released by fenfluramine, a serotonin transporter substrate that promotes non-vesicular 5-HT release, reproduces the pathway-specific serotonergic modulation previously observed with exogenously applied 5-HT. Fenfluramine selectively suppressed EPSPs evoked by lateral perforant path stimulation. A 5-HT₂ receptor antagonist markedly attenuated the fenfluramine-induced suppression, whereas blockade of 5-HT_1A receptors had no significant effect. These findings are consistent with the involvement of 5-HT₂ receptors in fenfluramine-induced modulation. Notably, fenfluramine-induced suppression of EPSPs was prominent in the ventral hippocampus but minimal in the dorsal hippocampus. ELISA measurements showed that fenfluramine evoked greater 5-HT release from ventral hippocampal slices than from dorsal ones. These findings highlight pathway- and region-specific serotonergic modulation of inputs from the entorhinal cortex to the dentate gyrus and suggest a potential mechanism underlying the functional specialization of the hippocampus along its dorso-ventral axis.