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.