Segregation of serotonin 5-HT2A and 5-HT3 receptors in inhibitory circuits of the primate cerebral cortex

An emerging concept of cortical network organization is that distinct segments of the pyramidal neuron tree are controlled by functionally diverse inhibitory microcircuits. We compared the expression of two serotonin receptor subtypes, the G-protein-coupled 5-hydroxytryptamine2A receptors and the ion-channel gating 5-HT3 receptors, in cortical neuron types, which control these microcircuits. Here we show, using light and electron microscopic immunocytochemical techniques, that 5-HT2A receptors are segregated from 5-HT3 receptors in the macaque cerebral cortex. 5-HT2A receptor immunolabel was found in pyramidal cells and also in GABAergic interneurons known to specialize in the perisomatic inhibition of pyramidal cells: large and medium-size parvalbumin- and calbindin-containing interneurons. In contrast, 5-HT3 label was only present in small GABA-, substance P receptor-, and calbindin-containing neurons and in medium-size calretinin-containing neurons: interneurons known to preferentially target the dendrites of pyramidal cells. This cellular segregation indicates a serotonin-receptor-specific segmentation of the GABAergic inhibitory actions along the pyramidal neuron tree.