Serotonin engages divergent 5-HT receptor pathways for cell type-resolved modulation of prefrontal layer 5 microcircuits.

Authors

Ramya Rama, Guanxiao Qi, Gabriele Radnikow, Danqing Yang, Dirk Feldmeyer

Published in

British journal of pharmacology. Jul 13, 2026. Epub Jul 13, 2026.

Abstract

Serotonin (5-HT) is a key neuromodulator in the prefrontal cortex (PFC), yet its cell type-specific effects across excitatory and inhibitory microcircuits remain incompletely understood. We aimed to determine how 5-HT shapes intrinsic excitability and synaptic transmission in defined neuronal populations of the medial PFC (mPFC).
We performed whole-cell recordings from morphologically and electrophysiologically characterised layer 5 (L5) neurons in rat mPFC. Pyramidal neurons were classified into adaptive-spiking high input resistance (AS_H), adaptive-spiking low input resistance (AS_L) and regular-spiking (RS) types; interneurons were categorised as non-fast-spiking (nFS), regular-fast-spiking (rFS) and stuttering-fast-spiking (sFS) interneurons. These cell types exhibited distinct membrane properties, firing patterns and axonal projections. We assessed serotonergic modulation using bath-applied 5-HT and subtype-specific receptor mechanisms.
5-HT produced divergent postsynaptic responses across pyramidal neuron subtypes: AS_H and RS neurons depolarised via 5-HT_2A receptor (5-HT_2AR) activation, whereas AS_L neurons exhibited 5-HT_1AR-mediated hyperpolarisation. Among interneurons, rFS and sFS cells depolarised through ionotropic 5-HT_3ARs, whereas nFS interneurons were largely unaffected. At the synaptic level, 5-HT suppressed excitatory synaptic transmission between pyramidal neurons via presynaptic 5-HT_1BRs. Selective activation of presynaptic 5-HT_3ARs enhanced inhibitory transmission from FS interneurons, whereas the overall effect of 5-HT on inhibitory synapses was suppressive, likely reflecting dominant presynaptic 5-HT_1BR-mediated inhibition.
Serotonin exerts complex, cell type-specific modulation of mPFC microcircuits through distinct somatodendritic and presynaptic receptor pathways. This balanced and targeted regulation provides a mechanistic basis for serotonergic influence on attention, cognitive flexibility, and emotional regulation.

PMID:
42444261
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.

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