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The Native Serotonin 5-HT5A Receptor: Electrophysiological Characterization in Rodent Cortex and 5-HT1A-Mediated Compensatory Plasticity in the Knock-Out Mouse

The 5-HT5A receptor is the least understood serotonin (5-HT) receptor. Here, we electrophysiologically identify and characterize a native 5-HT5A receptor current in acute ex vivo brain slices of adult rodent prefrontal cortex. In the presence of antagonists for the previously characterized 5-HT1A and 5-HT2 receptors, a proportion of layer V pyramidal neurons continue to show 5-HT-elicited outward currents in both rats and mice. These 5-HT currents are suppressed by the selective 5-HT5A antagonist, SB-699551, and are not observed in 5-HT5A receptor knock-out mice. Further characterization reveals that the 5-HT5A current is activated by submicromolar concentrations of 5-HT, is inwardly rectifying with a reversal potential near the equilibrium potential for K+ ions, and is suppressed by blockers of Kir3 channels. Finally, we observe that genetic deletion of the inhibitory 5-HT5A receptor results in an unexpected, large increase in the inhibitory 5-HT1A receptor currents. The presence of functional prefrontal 5-HT5A receptors in normal rodents along with compensatory plasticity in 5-HT5A receptor knock-out mice testifies to the significance of this receptor in the healthy prefrontal cortex.