The Role of Kv1.2-Containing Potassium Channels in Serotonin-Induced Glutamate Release from Thalamocortical Terminals in Rat Frontal Cortex

Summary

Blocking potassium channels that contain the Kv1.2 subunit triggers glutamate release in the rat prefrontal cortex, mimicking the effect of serotonin on thalamocortical terminals. The potassium channel blocker α-dendrotoxin (DTX), which selectively targets Kv1.1-, Kv1.2-, and Kv1.6-containing channels, induced excitatory postsynaptic currents (EPSCs) in layer V pyramidal neurons similar to those caused by serotonin acting on 5-HT2A receptors. Both DTX- and serotonin-induced EPSCs were blocked by tetrodotoxin and ω-agatoxin-IVA, suppressed by μ-opiates and thalamic lesions, and showed mutual occlusion, indicating a shared mechanism. This suggests that serotonin triggers glutamate release by inhibiting Kv1.2-containing potassium channels on thalamocortical terminals.

Study at a glance

Abstract

Serotonin 5-HT 2A receptors have been implicated in psychiatric illness and the psychotomimetic effects of hallucinogens. In brain slices, focal stimulation of 5-HT 2A receptors in rat prefrontal cortex results in dramatically increased glutamate release onto layer V pyramidal neurons, as measured by an increase in “spontaneous” (nonelectrically evoked) EPSCs. This glutamate release is blocked by tetrodotoxin (TTX) and is thought to involve local spiking in thalamocortical axon terminals; however, the detailed mechanism has remained unclear. Here, we investigate parallels in EPSCs induced by either serotonin or the potassium channel blockers 4-aminopyridine (4-AP) or α-dendrotoxin (DTX). DTX, a selective blocker of Kv1.1-, Kv1.2-, and Kv1.6-containing potassium channels, has been shown to release glutamate in cortical synaptosomes, presumably by inhibiting a subthreshold-activated, slowly inactivating potassium conductance. By comparing DTX with other potassium channel blockers, we found that the ability to induce EPSCs in cortical pyramidal neurons depends on affinity for Kv1.2 subunits. DTX-induced EPSCs are similar to 5-HT-induced EPSCs in terms of sensitivity to TTX and ω-agatoxin-IVA (a blocker of P-type calcium channels) and laminar selectivity. The involvement of thalamocortical terminals in DTX-induced EPSCs was confirmed by suppression of these EPSCs by μ-opiates and thalamic lesions. More directly, DTX-induced EPSCs substantially occlude those induced by 5-HT, suggesting a common mechanism of action. No occlusion by DTX was seen when EPSCs were induced by a nicotinic mechanism. These results indicate that blockade of Kv1.2-containing potassium channels is part of the mechanism underlying 5-HT-induced glutamate release from thalamocortical terminals.