Invited reviewSerotonergic regulation of neuronal excitability in the prefrontal cortex

The cerebral cortex receives a dense serotonergic innervation originating predominantly from the dorsal raphe nucleus. This innervation regulates cortical functioning by activating multiple serotonin receptors that are differentially expressed by pyramidal cells and interneurons. Electrophysiological studies in the prefrontal cortex indicate that receptors of the 5-HT1A and 5-HT2A subtypes are the main serotonin receptors regulating membrane excitability in pyramidal cells. Most pyramidal cells in layer V coexpress 5-HT1A and 5-HT2A receptors that together regulate how these neurons encode excitatory input into neuronal firing. In contrast, a subset of large pyramidal cells of deep layer V appears to express exclusively 5-HT2A receptors that depolarize and excite these cells. Serotonin also depolarizes and excites at least two classes of GABAergic interneurons by acting on 5-HT3 and 5-HT2A receptors. The differential expression of serotonin receptors in different pyramidal cells and interneurons is consistent with a growing appreciation of the anatomical, molecular and functional heterogeneity of pyramidal cells and interneurons of the cerebral cortex. These findings begin to lay the ground for a cellular-level understanding of the serotonergic regulation of the prefrontal cortex.

► In this study we review our current understanding of the effects of serotonin in prefrontal cortex. ► The cerebral cortex is innervated by serotonergic fibers originating from the dorsal raphe. ► Serotonin regulates layer V pyramidal cells predominantly via 5-HT2A and 5-HT1A receptors. ► These receptors are differentially expressed in distinct populations of pyramidal cells. ► Serotonin regulates GABAergic interneurons via 5-HT1A, 5-HT2A and 5-HT3 receptors.