Distribution of serotonin receptor 5-HT6 mRNA in rat neuronal subpopulations: A double in situ hybridization study

The 5-HT6 receptor (5-HT6R) is almost exclusively expressed in the brain and has emerged as a promising target for cognitive disorders, including Alzheimer's disease. In the present study, we have determined the cell types on which the 5-HT6R is expressed by colocalizing 5-HT6R mRNA with that of a range of neuronal and interneuronal markers in the rat brain. Here, we show that 5-HT6R mRNA was expressed at high levels in medium spiny neurons in caudate putamen and in nucleus accumbens, as well as in the olfactory tubercle. Striatal 5-HT6R mRNA was colocalized with both dopamine D1 and D2 receptor mRNA. 5-HT6R mRNA was moderately expressed in the hippocampus and throughout cortical regions in glutamatergic neurons coexpressing vGluT1. A subset of GAD67-positive GABAergic interneurons (approximately 15%) expressed 5-HT6R mRNA in the cortex and hippocampus, the majority of which belonged to the 5-HT3a receptor (5-HT3aR)-expressing subpopulation. In contrast, 5-HT6R mRNA was only expressed to a minor extent in the parvalbumin and somatostatin subpopulations. A subset of calbindin- and calretinin-positive GABAergic interneurons expressed 5-HT6R mRNA while only a very minor fraction of VIP or NPY interneurons in forebrain structures expressed 5-HT6R mRNA. Serotonergic, dopaminergic or cholinergic neurons did not express 5-HT6R mRNA. These data indicate that the 5-HT6R is located on GABAergic and glutamatergic principal neurons, and on a subset of interneurons mainly belonging to the 5-HT3aR subgroup suggesting that the 5-HT6R is positioned to regulate the balance between excitatory and inhibitory signaling in the brain. These data provide new insights into the mechanisms of 5-HT6R signaling.