Serotonergic regulation of neuronal excitability in the prefrontal cortex

Abstract

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-HT(1A) and 5-HT(2A) subtypes are the main serotonin receptors regulating membrane excitability in pyramidal cells. Most pyramidal cells in layer V coexpress 5-HT(1A) and 5-HT(2A) 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-HT(2A) receptors that depolarize and excite these cells. Serotonin also depolarizes and excites at least two classes of GABAergic interneurons by acting on 5-HT(3) and 5-HT(2A) 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.

Figure 1. 5-HT_2A receptors expression in the cerebral cortex

A. Expression of the 5-HT_2A receptor gene (HTR2A) in the mouse forebrain as revealed in a BAC transgenic mouse expressing EGFP under the control of the 5-HT_2A receptor promoter. Calibration bar: 2 mm. Aud: auditory cortex, Ent: entorhinal cortex, Orb: orbital cortex, PF: prefrontal cortex, S1: primary somatosensory cortex. Lower panel. Close up image depicting EGFP expression in an horizontal section through the prefrontal and orbital cortices. B. 5-HT_2A receptor expression as determined using an affinity purified anti-5-HT_2A receptor antibody. Notice the strong correspondence in EGFP in panel A and 5-HT_2A receptor expression in Panel B. Lower panel: 5-HT_2A receptor staining in the prefrontal cortex of a wild type (wt) mouse and a 5-HT_2A receptor knockout (5-HT_2AR KO) mouse. Calibration bar 200 μm. (Modified from Weber and Andrade, 2010).

Figure 2. 5-HT_1A and 5-HT₂ receptor-mediated responses in different neuronal subtypes in layer V of the prefrontal cortex

Activation of 5-HT_1A receptors elicits a membrane hyperpolarization in many if not most pyramidal cells of layer V of the rodent prefrontal cortex (a). In contrast, activation of 5-HT_2A receptors depolarizes a subset of pyramidal cells in deep layer V (b) and also a subset of GABAergic interneurons (c).