HIPPOCAMPAL INTERNEURONS ARE EXCITED VIA SEROTONIN-GATED ION CHANNELS

Serotonergic neurons of the median raphe nucleus heavily innervate hip pocampal GABAergic interneurons located in stratum radiatum of area CA 1, suggesting that this strong subcortical projection may modulate int erneuron excitability. Using whole cell patch-clamp recording from int erneurons in brain slices, we tested the effects of serotonin (5-HT) o n the physiological properties of these interneurons. Serotonin produc es a rapid inward current that persists when synaptic transmission is blocked by tetrodotoxin and cobalt, and is unaffected by ionotropic gl utamate and gamma-aminobutyric acid (GABA) receptor antagonists. The 5 -HT-induced current was independent of G-protein activation. Pharmacol ogical evidence indicates that 5-HT directly excites these interneuron s through activation of 5-HT3 receptors. At membrane potentials negati ve to -55 mV, the current-voltage (I-V) relationship of the 5-HT curre nt displays a region of negative slope conductance. Therefore the resp onse of interneurons to 5-HT strongly depends on membrane potential an d increases greatly as cells are depolarized. Removal of extracellular calcium, but not magnesium, increases the amplitude of 5-HT-induced c urrents and removes the region of negative slope conductance, thereby linearizing the I-V relationship. The axons of 5-HT-responsive interne urons ramify widely within CA1; some of these interneurons also projec t to and arborize extensively in the dentate gyrus. The organization o f these inhibitory connections strongly suggests that these cells regu late excitability of both CA1 pyramidal cells and dentate granule cell s. As our results indicate that 5-HT may mediate fast excitatory synap tic transmission onto these interneurons, serotonergic inputs can simu ltaneously modulate the output of both hippocampus and dentate gyrus.