The Largest Group of Superficial Neocortical GABAergic Interneurons Expresses Ionotropic Serotonin Receptors

A highly diverse population of neocortical GABAergic inhibitory interneurons has been implicated in multiple functions in information processing within cortical circuits. The diversity of cortical interneurons is determined during development and primarily depends on their embryonic origins either from the medial (MGE) or the caudal (CGE) ganglionic eminences. Although MGE-derived parvalbumin (PV)- or somatostatin (SST)-expressing interneurons are well characterized, less is known about the other types of cortical GABAergic interneurons, especially those of CGE lineage, because of the lack of specific neuronal markers for these interneuron subtypes. Using a bacterial artificial chromosome transgenic mouse line, we show that, in the somatosensory cortex of the mouse, the serotonin 5-hydroxytryptamine 3A (5-HT3A) receptor, the only ionotropic serotonergic receptor, is expressed in most, if not all, neocortical GABAergic interneurons that do not express PV or SST. Genetic fate mapping and neurochemical profile demonstrate that 5-HT3AR-expressing neurons include the entire spectrum of CGE-derived interneurons. We report that, in addition to serotonergic responsiveness via 5-HT(3A)Rs, acetylcholine also depolarizes 5-HT3AR-expressing neurons via nicotinic receptors. 5-HT3AR-expressing neurons in thalamocortical (TC) recipient areas receive weak but direct monosynaptic inputs from the thalamus. TC input depolarizes a subset of TC-recipient 5-HT3AR neurons as strongly as fast-spiking cells, in part because of their high input resistance. Hence, fast modulation of serotonergic and cholinergic transmission may influence cortical activity through an enhancement of GABAergic synaptic transmission from 5-HT3AR-expressing neurons during sensory process depending on different behavioral states.